US20220220117A1 - 9-substituted amino triazolo quinazoline derivatives as adenosine receptor antagonists, pharmaceutical compositions and their use - Google Patents
9-substituted amino triazolo quinazoline derivatives as adenosine receptor antagonists, pharmaceutical compositions and their use Download PDFInfo
- Publication number
- US20220220117A1 US20220220117A1 US17/657,515 US202217657515A US2022220117A1 US 20220220117 A1 US20220220117 A1 US 20220220117A1 US 202217657515 A US202217657515 A US 202217657515A US 2022220117 A1 US2022220117 A1 US 2022220117A1
- Authority
- US
- United States
- Prior art keywords
- cancer
- mixture
- mmol
- compound
- pyrazol
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- -1 9-substituted amino triazolo quinazoline Chemical class 0.000 title abstract description 36
- 239000008194 pharmaceutical composition Substances 0.000 title abstract description 17
- 229940121359 adenosine receptor antagonist Drugs 0.000 title 1
- 239000000296 purinergic P1 receptor antagonist Substances 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 208
- 238000000034 method Methods 0.000 claims abstract description 86
- 150000003839 salts Chemical class 0.000 claims abstract description 77
- 239000003814 drug Substances 0.000 claims abstract description 47
- 229940124597 therapeutic agent Drugs 0.000 claims abstract description 26
- 206010028980 Neoplasm Diseases 0.000 claims description 112
- 201000011510 cancer Diseases 0.000 claims description 72
- 229940124060 PD-1 antagonist Drugs 0.000 claims description 36
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 33
- 229960002621 pembrolizumab Drugs 0.000 claims description 28
- 229910052731 fluorine Inorganic materials 0.000 claims description 21
- 229960003301 nivolumab Drugs 0.000 claims description 19
- 206010008342 Cervix carcinoma Diseases 0.000 claims description 18
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 claims description 18
- 229960003852 atezolizumab Drugs 0.000 claims description 18
- 201000010881 cervical cancer Diseases 0.000 claims description 18
- 208000002154 non-small cell lung carcinoma Diseases 0.000 claims description 16
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 claims description 16
- 208000013056 classic Hodgkin lymphoma Diseases 0.000 claims description 14
- 208000008839 Kidney Neoplasms Diseases 0.000 claims description 13
- 208000014829 head and neck neoplasm Diseases 0.000 claims description 13
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 12
- 206010038389 Renal cancer Diseases 0.000 claims description 12
- 201000010982 kidney cancer Diseases 0.000 claims description 12
- 208000026037 malignant tumor of neck Diseases 0.000 claims description 12
- 206010009944 Colon cancer Diseases 0.000 claims description 11
- 206010017758 gastric cancer Diseases 0.000 claims description 11
- 206010073071 hepatocellular carcinoma Diseases 0.000 claims description 11
- 208000032818 Microsatellite Instability Diseases 0.000 claims description 10
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 10
- 206010036711 Primary mediastinal large B-cell lymphomas Diseases 0.000 claims description 10
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 10
- 231100000844 hepatocellular carcinoma Toxicity 0.000 claims description 10
- 201000001441 melanoma Diseases 0.000 claims description 10
- 230000001394 metastastic effect Effects 0.000 claims description 10
- 206010061289 metastatic neoplasm Diseases 0.000 claims description 10
- 201000011549 stomach cancer Diseases 0.000 claims description 10
- 206010044412 transitional cell carcinoma Diseases 0.000 claims description 10
- 208000023747 urothelial carcinoma Diseases 0.000 claims description 10
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 9
- 206010060862 Prostate cancer Diseases 0.000 claims description 9
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 9
- 229910052801 chlorine Inorganic materials 0.000 claims description 9
- 229950009791 durvalumab Drugs 0.000 claims description 9
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 9
- 201000002528 pancreatic cancer Diseases 0.000 claims description 9
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 9
- 206010006187 Breast cancer Diseases 0.000 claims description 8
- 208000026310 Breast neoplasm Diseases 0.000 claims description 8
- 229950002916 avelumab Drugs 0.000 claims description 8
- 208000014018 liver neoplasm Diseases 0.000 claims description 8
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 8
- 201000009030 Carcinoma Diseases 0.000 claims description 7
- 208000000461 Esophageal Neoplasms Diseases 0.000 claims description 7
- 206010027406 Mesothelioma Diseases 0.000 claims description 7
- 206010030155 Oesophageal carcinoma Diseases 0.000 claims description 7
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 7
- 201000004101 esophageal cancer Diseases 0.000 claims description 7
- 125000004076 pyridyl group Chemical group 0.000 claims description 7
- 206010061424 Anal cancer Diseases 0.000 claims description 6
- 208000007860 Anus Neoplasms Diseases 0.000 claims description 6
- 206010005003 Bladder cancer Diseases 0.000 claims description 6
- 206010017993 Gastrointestinal neoplasms Diseases 0.000 claims description 6
- 208000034578 Multiple myelomas Diseases 0.000 claims description 6
- 206010033128 Ovarian cancer Diseases 0.000 claims description 6
- 206010035226 Plasma cell myeloma Diseases 0.000 claims description 6
- 206010039491 Sarcoma Diseases 0.000 claims description 6
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 claims description 6
- 201000011165 anus cancer Diseases 0.000 claims description 6
- 201000009036 biliary tract cancer Diseases 0.000 claims description 6
- 208000020790 biliary tract neoplasm Diseases 0.000 claims description 6
- 201000007270 liver cancer Diseases 0.000 claims description 6
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 6
- 125000001425 triazolyl group Chemical group 0.000 claims description 6
- 201000005112 urinary bladder cancer Diseases 0.000 claims description 6
- 206010014733 Endometrial cancer Diseases 0.000 claims description 5
- 206010014759 Endometrial neoplasm Diseases 0.000 claims description 5
- 201000005243 lung squamous cell carcinoma Diseases 0.000 claims description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 42
- 238000002360 preparation method Methods 0.000 abstract description 39
- 101150078577 Adora2b gene Proteins 0.000 abstract description 37
- 101150051188 Adora2a gene Proteins 0.000 abstract description 24
- 201000010099 disease Diseases 0.000 abstract description 20
- 239000005557 antagonist Substances 0.000 abstract description 13
- 108010085277 Adenosine A2A receptor Proteins 0.000 abstract description 10
- 102000007471 Adenosine A2A receptor Human genes 0.000 abstract description 8
- 102000007470 Adenosine A2B Receptor Human genes 0.000 abstract description 6
- 108010085273 Adenosine A2B receptor Proteins 0.000 abstract description 6
- 230000001404 mediated effect Effects 0.000 abstract description 6
- 239000013543 active substance Substances 0.000 abstract description 5
- 239000000203 mixture Substances 0.000 description 519
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 370
- 239000000543 intermediate Substances 0.000 description 339
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 233
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 217
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 182
- 239000002904 solvent Substances 0.000 description 131
- 235000019439 ethyl acetate Nutrition 0.000 description 115
- 239000003607 modifier Substances 0.000 description 105
- 239000006184 cosolvent Substances 0.000 description 104
- 239000003480 eluent Substances 0.000 description 97
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 97
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 96
- 239000000706 filtrate Substances 0.000 description 84
- 239000000243 solution Substances 0.000 description 83
- 238000010898 silica gel chromatography Methods 0.000 description 82
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 78
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 75
- 229910001868 water Inorganic materials 0.000 description 74
- 239000012044 organic layer Substances 0.000 description 67
- 239000003795 chemical substances by application Substances 0.000 description 62
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 61
- 238000005160 1H NMR spectroscopy Methods 0.000 description 60
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 59
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 57
- 238000004808 supercritical fluid chromatography Methods 0.000 description 57
- 229910052757 nitrogen Chemical group 0.000 description 53
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 50
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical class OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 49
- 238000005516 engineering process Methods 0.000 description 48
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 46
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 42
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 42
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 42
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 41
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 41
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 35
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 32
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 31
- 229910052938 sodium sulfate Inorganic materials 0.000 description 30
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 29
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 description 28
- 239000007832 Na2SO4 Substances 0.000 description 28
- BTANRVKWQNVYAZ-UHFFFAOYSA-N butan-2-ol Chemical compound CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 description 28
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 27
- 230000015572 biosynthetic process Effects 0.000 description 27
- 238000006243 chemical reaction Methods 0.000 description 27
- 230000000875 corresponding effect Effects 0.000 description 27
- 229910052739 hydrogen Inorganic materials 0.000 description 27
- 238000003786 synthesis reaction Methods 0.000 description 27
- OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 description 26
- 239000003208 petroleum Substances 0.000 description 25
- 238000004007 reversed phase HPLC Methods 0.000 description 25
- 239000007858 starting material Substances 0.000 description 25
- 239000012258 stirred mixture Substances 0.000 description 24
- 102100040678 Programmed cell death protein 1 Human genes 0.000 description 23
- 239000012267 brine Substances 0.000 description 23
- 239000010410 layer Substances 0.000 description 23
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 23
- 238000000926 separation method Methods 0.000 description 22
- 208000035475 disorder Diseases 0.000 description 21
- 239000007787 solid Substances 0.000 description 21
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 21
- 239000002552 dosage form Substances 0.000 description 20
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 20
- 239000000047 product Substances 0.000 description 20
- 239000003643 water by type Substances 0.000 description 20
- 101710089372 Programmed cell death protein 1 Proteins 0.000 description 19
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Substances CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 description 19
- 239000000741 silica gel Substances 0.000 description 19
- 229910002027 silica gel Inorganic materials 0.000 description 19
- HPXRVTGHNJAIIH-UHFFFAOYSA-N cyclohexanol Chemical compound OC1CCCCC1 HPXRVTGHNJAIIH-UHFFFAOYSA-N 0.000 description 18
- 229920006395 saturated elastomer Polymers 0.000 description 18
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 17
- 238000004809 thin layer chromatography Methods 0.000 description 17
- 238000009472 formulation Methods 0.000 description 16
- 102100024216 Programmed cell death 1 ligand 1 Human genes 0.000 description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 15
- ZKSMSCZAWFJIIQ-UHFFFAOYSA-N piperidine-3-carbohydrazide Chemical compound NNC(=O)C1CCCNC1 ZKSMSCZAWFJIIQ-UHFFFAOYSA-N 0.000 description 14
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 14
- NDOVLWQBFFJETK-UHFFFAOYSA-N 1,4-thiazinane 1,1-dioxide Chemical compound O=S1(=O)CCNCC1 NDOVLWQBFFJETK-UHFFFAOYSA-N 0.000 description 13
- 239000002126 C01EB10 - Adenosine Substances 0.000 description 13
- 102100032373 Coiled-coil domain-containing protein 85B Human genes 0.000 description 13
- 101000868814 Homo sapiens Coiled-coil domain-containing protein 85B Proteins 0.000 description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 13
- 229960005305 adenosine Drugs 0.000 description 13
- LVTYICIALWPMFW-UHFFFAOYSA-N diisopropanolamine Chemical compound CC(O)CNCC(C)O LVTYICIALWPMFW-UHFFFAOYSA-N 0.000 description 13
- 125000001072 heteroaryl group Chemical group 0.000 description 13
- 125000001424 substituent group Chemical group 0.000 description 13
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 12
- 102100024213 Programmed cell death 1 ligand 2 Human genes 0.000 description 12
- 239000000460 chlorine Substances 0.000 description 12
- 229910052760 oxygen Inorganic materials 0.000 description 12
- 235000017557 sodium bicarbonate Nutrition 0.000 description 12
- WVGCPEDBFHEHEZ-UHFFFAOYSA-N 4-bromo-1h-pyrazole Chemical compound BrC=1C=NNC=1 WVGCPEDBFHEHEZ-UHFFFAOYSA-N 0.000 description 11
- 101000611936 Homo sapiens Programmed cell death protein 1 Proteins 0.000 description 11
- 229910052799 carbon Inorganic materials 0.000 description 11
- 210000003128 head Anatomy 0.000 description 11
- 239000001257 hydrogen Substances 0.000 description 11
- 230000005764 inhibitory process Effects 0.000 description 11
- 239000011734 sodium Substances 0.000 description 11
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 10
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 10
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 10
- 101001117317 Homo sapiens Programmed cell death 1 ligand 1 Proteins 0.000 description 10
- 239000005909 Kieselgur Substances 0.000 description 10
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 10
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 10
- 150000001502 aryl halides Chemical class 0.000 description 10
- 229940079593 drug Drugs 0.000 description 10
- 238000001914 filtration Methods 0.000 description 10
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 10
- 125000006413 ring segment Chemical group 0.000 description 10
- 239000012453 solvate Substances 0.000 description 10
- 230000001225 therapeutic effect Effects 0.000 description 10
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 10
- 229960005486 vaccine Drugs 0.000 description 10
- 108010074708 B7-H1 Antigen Proteins 0.000 description 9
- JXBWWEYTUXDSLL-GOSISDBHSA-N C1=C(C(=CC2=C1C1=NC([C@@H]3CCCN(C=4C=NNC=4C)C3)=NN1C(=N2)NCC1=CC=C(OC)C=C1OC)OC)F Chemical compound C1=C(C(=CC2=C1C1=NC([C@@H]3CCCN(C=4C=NNC=4C)C3)=NN1C(=N2)NCC1=CC=C(OC)C=C1OC)OC)F JXBWWEYTUXDSLL-GOSISDBHSA-N 0.000 description 9
- PINIGGOUPYDUDA-UHFFFAOYSA-N COC1=C(CN=C=NC2=C(C#N)C=C(C(=C2)OC)F)C=CC(=C1)OC Chemical compound COC1=C(CN=C=NC2=C(C#N)C=C(C(=C2)OC)F)C=CC(=C1)OC PINIGGOUPYDUDA-UHFFFAOYSA-N 0.000 description 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 9
- IVERFSUDJLTLTD-OAHLLOKOSA-N N-[(2,4-dimethoxyphenyl)methyl]-9-fluoro-8-methoxy-2-[(3R)-piperidin-3-yl]-[1,2,4]triazolo[1,5-c]quinazolin-5-amine Chemical compound C1=C(C(=CC2=C1C1=NC(=NN1C(=N2)NCC1=C(OC)C=C(OC)C=C1)[C@@H]1CCCNC1)OC)F IVERFSUDJLTLTD-OAHLLOKOSA-N 0.000 description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
- 239000004480 active ingredient Substances 0.000 description 9
- 125000004429 atom Chemical group 0.000 description 9
- 210000004027 cell Anatomy 0.000 description 9
- 229960004132 diethyl ether Drugs 0.000 description 9
- 125000005842 heteroatom Chemical group 0.000 description 9
- 125000000623 heterocyclic group Chemical group 0.000 description 9
- 239000001301 oxygen Substances 0.000 description 9
- 239000012071 phase Substances 0.000 description 9
- 229940002612 prodrug Drugs 0.000 description 9
- 239000000651 prodrug Substances 0.000 description 9
- 229910052717 sulfur Inorganic materials 0.000 description 9
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 8
- 125000004122 cyclic group Chemical group 0.000 description 8
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 description 8
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 8
- 239000003112 inhibitor Substances 0.000 description 8
- 239000000546 pharmaceutical excipient Substances 0.000 description 8
- IZEDOPGEJFXLNB-UHFFFAOYSA-N 1-(4-bromo-3-methylpyrazol-1-yl)-2-methylpropan-2-ol Chemical compound BrC=1C(=NN(C=1)CC(C)(O)C)C IZEDOPGEJFXLNB-UHFFFAOYSA-N 0.000 description 7
- 102000009346 Adenosine receptors Human genes 0.000 description 7
- 108050000203 Adenosine receptors Proteins 0.000 description 7
- 238000005481 NMR spectroscopy Methods 0.000 description 7
- 210000001744 T-lymphocyte Anatomy 0.000 description 7
- 125000000217 alkyl group Chemical group 0.000 description 7
- 150000001412 amines Chemical class 0.000 description 7
- 239000012298 atmosphere Substances 0.000 description 7
- 230000027455 binding Effects 0.000 description 7
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 7
- 229910000024 caesium carbonate Inorganic materials 0.000 description 7
- 125000004432 carbon atom Chemical group C* 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- 102000048362 human PDCD1 Human genes 0.000 description 7
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 7
- 239000012299 nitrogen atmosphere Substances 0.000 description 7
- 229910000027 potassium carbonate Inorganic materials 0.000 description 7
- 230000008569 process Effects 0.000 description 7
- 239000011541 reaction mixture Substances 0.000 description 7
- 210000002966 serum Anatomy 0.000 description 7
- 238000006467 substitution reaction Methods 0.000 description 7
- MOQLLNFUQGHFMH-UHFFFAOYSA-N 1-(4-bromo-5-methylpyrazol-1-yl)-2-methylpropan-2-ol Chemical compound BrC=1C=NN(C=1C)CC(C)(O)C MOQLLNFUQGHFMH-UHFFFAOYSA-N 0.000 description 6
- IOUKCMFUEJBHER-UHFFFAOYSA-N 1-(4-bromopyrazol-1-yl)-2-methylpropan-2-ol Chemical compound CC(C)(O)CN1C=C(Br)C=N1 IOUKCMFUEJBHER-UHFFFAOYSA-N 0.000 description 6
- ZWDDLPJTGFCTGE-UHFFFAOYSA-N 4-bromo-1-[[1-(oxan-2-yloxy)cyclobutyl]methyl]pyrazole Chemical compound BrC=1C=NN(C=1)CC1(CCC1)OC1OCCCC1 ZWDDLPJTGFCTGE-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- KVEIZHPKKXKYGF-HHHXNRCGSA-N COC1=C(CNC2=NC=3C=C(C(=CC=3C=3N2N=C(N=3)[C@@H]2OCCN(C2)C=2C(=NN(C=2)CC(C)(O)C)C)F)OC)C=CC(=C1)OC Chemical compound COC1=C(CNC2=NC=3C=C(C(=CC=3C=3N2N=C(N=3)[C@@H]2OCCN(C2)C=2C(=NN(C=2)CC(C)(O)C)C)F)OC)C=CC(=C1)OC KVEIZHPKKXKYGF-HHHXNRCGSA-N 0.000 description 6
- 101100407308 Mus musculus Pdcd1lg2 gene Proteins 0.000 description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 6
- 108700030875 Programmed Cell Death 1 Ligand 2 Proteins 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 229910021529 ammonia Inorganic materials 0.000 description 6
- 125000003118 aryl group Chemical group 0.000 description 6
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 6
- 102000048776 human CD274 Human genes 0.000 description 6
- 230000000670 limiting effect Effects 0.000 description 6
- 229940044551 receptor antagonist Drugs 0.000 description 6
- 239000002464 receptor antagonist Substances 0.000 description 6
- 206010041823 squamous cell carcinoma Diseases 0.000 description 6
- 208000017572 squamous cell neoplasm Diseases 0.000 description 6
- 239000000725 suspension Substances 0.000 description 6
- 210000004881 tumor cell Anatomy 0.000 description 6
- WJLKJRCGDXKJDQ-UHFFFAOYSA-N 1-(4-aminopyrazol-1-yl)-2-methylpropan-2-ol Chemical compound CC(C)(O)CN1C=C(N)C=N1 WJLKJRCGDXKJDQ-UHFFFAOYSA-N 0.000 description 5
- PLPRTYIZKXNANG-UHFFFAOYSA-N 3-ethyl-5-fluoropiperidine-1,3-dicarboxylic acid Chemical compound CCC1(CC(CN(C1)C(=O)O)F)C(=O)O PLPRTYIZKXNANG-UHFFFAOYSA-N 0.000 description 5
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 5
- BIIUSNNKNOZUOG-OAHLLOKOSA-N C12=CC(=C(OC)C=C2N=C(N2C1=NC(=N2)[C@@H]1CCCN(C=2C=NN(C=2)CCCC(=O)C)C1)N)F Chemical compound C12=CC(=C(OC)C=C2N=C(N2C1=NC(=N2)[C@@H]1CCCN(C=2C=NN(C=2)CCCC(=O)C)C1)N)F BIIUSNNKNOZUOG-OAHLLOKOSA-N 0.000 description 5
- UDCSWGFVVLZOHP-HHHXNRCGSA-N C1=C(C(=CC2=C1C1=NC([C@@H]3OCCN(C3)C3=C(C)N(N=C3)CC(O)(C)C)=NN1C(=N2)NCC1=C(OC)C=C(OC)C=C1)OC)F Chemical compound C1=C(C(=CC2=C1C1=NC([C@@H]3OCCN(C3)C3=C(C)N(N=C3)CC(O)(C)C)=NN1C(=N2)NCC1=C(OC)C=C(OC)C=C1)OC)F UDCSWGFVVLZOHP-HHHXNRCGSA-N 0.000 description 5
- 101001117312 Homo sapiens Programmed cell death 1 ligand 2 Proteins 0.000 description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 5
- 206010027480 Metastatic malignant melanoma Diseases 0.000 description 5
- 208000036142 Viral infection Diseases 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 238000004458 analytical method Methods 0.000 description 5
- 239000000427 antigen Substances 0.000 description 5
- 102000036639 antigens Human genes 0.000 description 5
- 108091007433 antigens Proteins 0.000 description 5
- 150000001718 carbodiimides Chemical class 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 125000000753 cycloalkyl group Chemical group 0.000 description 5
- 239000003937 drug carrier Substances 0.000 description 5
- 235000019253 formic acid Nutrition 0.000 description 5
- 208000015181 infectious disease Diseases 0.000 description 5
- 238000001990 intravenous administration Methods 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- NXPHGHWWQRMDIA-UHFFFAOYSA-M magnesium;carbanide;bromide Chemical compound [CH3-].[Mg+2].[Br-] NXPHGHWWQRMDIA-UHFFFAOYSA-M 0.000 description 5
- 208000021039 metastatic melanoma Diseases 0.000 description 5
- 125000002950 monocyclic group Chemical group 0.000 description 5
- 125000006578 monocyclic heterocycloalkyl group Chemical group 0.000 description 5
- 238000000746 purification Methods 0.000 description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 5
- 230000000306 recurrent effect Effects 0.000 description 5
- 239000012279 sodium borohydride Substances 0.000 description 5
- 229910000033 sodium borohydride Inorganic materials 0.000 description 5
- 229910000104 sodium hydride Inorganic materials 0.000 description 5
- 239000000758 substrate Substances 0.000 description 5
- 208000024891 symptom Diseases 0.000 description 5
- DABYYYLRDBQJTK-MRVPVSSYSA-N tert-butyl (3r)-3-(hydrazinecarbonyl)piperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)NN)C1 DABYYYLRDBQJTK-MRVPVSSYSA-N 0.000 description 5
- 230000009385 viral infection Effects 0.000 description 5
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 4
- APWRZPQBPCAXFP-UHFFFAOYSA-N 1-(1-oxo-2H-isoquinolin-5-yl)-5-(trifluoromethyl)-N-[2-(trifluoromethyl)pyridin-4-yl]pyrazole-4-carboxamide Chemical compound O=C1NC=CC2=C(C=CC=C12)N1N=CC(=C1C(F)(F)F)C(=O)NC1=CC(=NC=C1)C(F)(F)F APWRZPQBPCAXFP-UHFFFAOYSA-N 0.000 description 4
- ABDDQTDRAHXHOC-QMMMGPOBSA-N 1-[(7s)-5,7-dihydro-4h-thieno[2,3-c]pyran-7-yl]-n-methylmethanamine Chemical compound CNC[C@@H]1OCCC2=C1SC=C2 ABDDQTDRAHXHOC-QMMMGPOBSA-N 0.000 description 4
- AFABGHUZZDYHJO-UHFFFAOYSA-N 2-Methylpentane Chemical compound CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 description 4
- BOWBJKBEGDAQDT-UHFFFAOYSA-N 2-amino-5-fluoro-4-methoxybenzonitrile Chemical compound COc1cc(N)c(cc1F)C#N BOWBJKBEGDAQDT-UHFFFAOYSA-N 0.000 description 4
- WNEODWDFDXWOLU-QHCPKHFHSA-N 3-[3-(hydroxymethyl)-4-[1-methyl-5-[[5-[(2s)-2-methyl-4-(oxetan-3-yl)piperazin-1-yl]pyridin-2-yl]amino]-6-oxopyridin-3-yl]pyridin-2-yl]-7,7-dimethyl-1,2,6,8-tetrahydrocyclopenta[3,4]pyrrolo[3,5-b]pyrazin-4-one Chemical compound C([C@@H](N(CC1)C=2C=NC(NC=3C(N(C)C=C(C=3)C=3C(=C(N4C(C5=CC=6CC(C)(C)CC=6N5CC4)=O)N=CC=3)CO)=O)=CC=2)C)N1C1COC1 WNEODWDFDXWOLU-QHCPKHFHSA-N 0.000 description 4
- BUQUSXJZSCAUNC-UHFFFAOYSA-N 4-bromo-1-[2-(oxan-2-yloxy)cyclopentyl]pyrazole Chemical compound BrC=1C=NN(C=1)C1C(CCC1)OC1OCCCC1 BUQUSXJZSCAUNC-UHFFFAOYSA-N 0.000 description 4
- XORHNJQEWQGXCN-UHFFFAOYSA-N 4-nitro-1h-pyrazole Chemical compound [O-][N+](=O)C=1C=NNC=1 XORHNJQEWQGXCN-UHFFFAOYSA-N 0.000 description 4
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 4
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- OQMMMQPJDXPRJU-MTATWXBHSA-N C1=C(C(=CC2=C1C1=NC(=NN1C(=N2)N)[C@@H]1CCCN(C=2C=NN(C=2)C2CCC2=O)C1)OC)F Chemical compound C1=C(C(=CC2=C1C1=NC(=NN1C(=N2)N)[C@@H]1CCCN(C=2C=NN(C=2)C2CCC2=O)C1)OC)F OQMMMQPJDXPRJU-MTATWXBHSA-N 0.000 description 4
- UJKSRDXNLUZKBW-UHFFFAOYSA-N C1=C(C=C(C2=C1C(NNC(=O)C1CCCN(C1)C1=CN(N=C1)C)=NC(=N2)N)OC)F Chemical compound C1=C(C=C(C2=C1C(NNC(=O)C1CCCN(C1)C1=CN(N=C1)C)=NC(=N2)N)OC)F UJKSRDXNLUZKBW-UHFFFAOYSA-N 0.000 description 4
- GBRYDSGBIBWXIT-UHFFFAOYSA-N C=1C(=CN(N=1)C1CCC1=O)Br Chemical compound C=1C(=CN(N=1)C1CCC1=O)Br GBRYDSGBIBWXIT-UHFFFAOYSA-N 0.000 description 4
- FCJZSPLZUUCTJT-UHFFFAOYSA-N COC1=C(CN=C=NC2=C(C#N)C=C(C=C2OC)F)C=CC(=C1)OC Chemical compound COC1=C(CN=C=NC2=C(C#N)C=C(C=C2OC)F)C=CC(=C1)OC FCJZSPLZUUCTJT-UHFFFAOYSA-N 0.000 description 4
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 4
- 108010017213 Granulocyte-Macrophage Colony-Stimulating Factor Proteins 0.000 description 4
- 102100039620 Granulocyte-macrophage colony-stimulating factor Human genes 0.000 description 4
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 4
- 150000001204 N-oxides Chemical class 0.000 description 4
- YZCKVEUIGOORGS-IGMARMGPSA-N Protium Chemical compound [1H] YZCKVEUIGOORGS-IGMARMGPSA-N 0.000 description 4
- 241000720974 Protium Species 0.000 description 4
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 4
- RHQDFWAXVIIEBN-UHFFFAOYSA-N Trifluoroethanol Chemical compound OCC(F)(F)F RHQDFWAXVIIEBN-UHFFFAOYSA-N 0.000 description 4
- 230000002378 acidificating effect Effects 0.000 description 4
- 238000002648 combination therapy Methods 0.000 description 4
- NKLCNNUWBJBICK-UHFFFAOYSA-N dess–martin periodinane Chemical compound C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 description 4
- BVAWLUIJPJIYMF-UHFFFAOYSA-N ethyl 1-(1-methylpyrazol-4-yl)piperidine-3-carboxylate Chemical compound C1C(C(=O)OCC)CCCN1C1=CN(C)N=C1 BVAWLUIJPJIYMF-UHFFFAOYSA-N 0.000 description 4
- 238000013265 extended release Methods 0.000 description 4
- 239000000499 gel Substances 0.000 description 4
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 4
- 210000004072 lung Anatomy 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 230000007246 mechanism Effects 0.000 description 4
- 210000004985 myeloid-derived suppressor cell Anatomy 0.000 description 4
- VVWRJUBEIPHGQF-MDZDMXLPSA-N propan-2-yl (ne)-n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)\N=N\C(=O)OC(C)C VVWRJUBEIPHGQF-MDZDMXLPSA-N 0.000 description 4
- ZDYVRSLAEXCVBX-UHFFFAOYSA-N pyridinium p-toluenesulfonate Chemical compound C1=CC=[NH+]C=C1.CC1=CC=C(S([O-])(=O)=O)C=C1 ZDYVRSLAEXCVBX-UHFFFAOYSA-N 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- 230000004044 response Effects 0.000 description 4
- 238000001228 spectrum Methods 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 125000004434 sulfur atom Chemical group 0.000 description 4
- 230000004083 survival effect Effects 0.000 description 4
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 4
- HJUGFYREWKUQJT-UHFFFAOYSA-N tetrabromomethane Chemical compound BrC(Br)(Br)Br HJUGFYREWKUQJT-UHFFFAOYSA-N 0.000 description 4
- 238000002560 therapeutic procedure Methods 0.000 description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 4
- 238000001851 vibrational circular dichroism spectroscopy Methods 0.000 description 4
- PKQBQVSDJYRHRW-UHFFFAOYSA-N (1-hydroxycyclobutyl)methyl methanesulfonate Chemical compound CS(=O)(=O)OCC1(O)CCC1 PKQBQVSDJYRHRW-UHFFFAOYSA-N 0.000 description 3
- UEDUZYXWOZILMR-UHFFFAOYSA-N (3-methyloxetan-3-yl)methyl methanesulfonate Chemical compound CS(=O)(=O)OCC1(C)COC1 UEDUZYXWOZILMR-UHFFFAOYSA-N 0.000 description 3
- MAYZWDRUFKUGGP-VIFPVBQESA-N (3s)-1-[5-tert-butyl-3-[(1-methyltetrazol-5-yl)methyl]triazolo[4,5-d]pyrimidin-7-yl]pyrrolidin-3-ol Chemical compound CN1N=NN=C1CN1C2=NC(C(C)(C)C)=NC(N3C[C@@H](O)CC3)=C2N=N1 MAYZWDRUFKUGGP-VIFPVBQESA-N 0.000 description 3
- AQVZIFBABRFRML-UHFFFAOYSA-N (4-bromo-1-ethylpyrazol-3-yl)methanol Chemical compound CCN1C=C(Br)C(CO)=N1 AQVZIFBABRFRML-UHFFFAOYSA-N 0.000 description 3
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 description 3
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 description 3
- QJFJAFSGKVGUSU-UHFFFAOYSA-N 1-(1,4-dioxaspiro[4.5]decan-8-yl)pyrazol-4-amine Chemical compound O1CCOC11CCC(CC1)N1N=CC(=C1)N QJFJAFSGKVGUSU-UHFFFAOYSA-N 0.000 description 3
- SEQLKMHWQQPXKP-UHFFFAOYSA-N 1-(2-cyano-4-fluoro-5-methoxyphenyl)-3-[(2,4-dimethoxyphenyl)methyl]urea Chemical compound C1=C(C(=CC(=C1C#N)NC(=O)NCC1=C(C=C(OC)C=C1)OC)OC)F SEQLKMHWQQPXKP-UHFFFAOYSA-N 0.000 description 3
- JLSWUCYAPQZIFC-UHFFFAOYSA-N 1-(4-bromo-3-cyclopropylpyrazol-1-yl)-2-methylpropan-2-ol Chemical compound N1(CC(O)(C)C)N=C(C(=C1)Br)C1CC1 JLSWUCYAPQZIFC-UHFFFAOYSA-N 0.000 description 3
- VPRFXHMQLDVHSK-UHFFFAOYSA-N 1-[(4-bromopyrazol-1-yl)methyl]cyclobutan-1-ol Chemical compound BrC=1C=NN(C=1)CC1(CCC1)O VPRFXHMQLDVHSK-UHFFFAOYSA-N 0.000 description 3
- YCXCRFGBFZTUSU-SNVBAGLBSA-N 1-o-tert-butyl 3-o-ethyl (3r)-piperidine-1,3-dicarboxylate Chemical compound CCOC(=O)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1 YCXCRFGBFZTUSU-SNVBAGLBSA-N 0.000 description 3
- VNLLBTSMSLITGU-UHFFFAOYSA-N 1-o-tert-butyl 3-o-methyl 5-methylpiperidine-1,3-dicarboxylate Chemical compound COC(=O)C1CC(C)CN(C(=O)OC(C)(C)C)C1 VNLLBTSMSLITGU-UHFFFAOYSA-N 0.000 description 3
- XEZNGIUYQVAUSS-UHFFFAOYSA-N 18-crown-6 Chemical compound C1COCCOCCOCCOCCOCCO1 XEZNGIUYQVAUSS-UHFFFAOYSA-N 0.000 description 3
- HZNVUJQVZSTENZ-UHFFFAOYSA-N 2,3-dichloro-5,6-dicyano-p-benzoquinone Substances ClC1=C(Cl)C(=O)C(C#N)=C(C#N)C1=O HZNVUJQVZSTENZ-UHFFFAOYSA-N 0.000 description 3
- VXWAYRNIPLNCNN-UHFFFAOYSA-N 2-(4-aminopyrazol-1-yl)-2-methylpropan-1-ol Chemical compound OCC(C)(C)N1C=C(N)C=N1 VXWAYRNIPLNCNN-UHFFFAOYSA-N 0.000 description 3
- RJOYLRYKPNMCIF-UHFFFAOYSA-N 2-(4-bromopyrazol-1-yl)-1-methylcyclobutan-1-ol Chemical compound C=1C(=CN(N=1)C1CCC1(O)C)Br RJOYLRYKPNMCIF-UHFFFAOYSA-N 0.000 description 3
- QNKVONNYXJUSKP-UHFFFAOYSA-N 2-(4-bromopyrazol-1-yl)-2-methylpropan-1-ol Chemical compound OCC(C)(C)N1C=C(Br)C=N1 QNKVONNYXJUSKP-UHFFFAOYSA-N 0.000 description 3
- DTKBMJOGMRGMGS-UHFFFAOYSA-N 2-amino-4-(difluoromethoxy)-5-fluorobenzonitrile Chemical compound NC1=C(C#N)C=C(C(=C1)OC(F)F)F DTKBMJOGMRGMGS-UHFFFAOYSA-N 0.000 description 3
- RBRQDLJMXKZRJN-UHFFFAOYSA-N 2-amino-6-fluoro-8-methoxy-3H-quinazolin-4-one Chemical compound NC1=NC2=C(C=C(C=C2C(=N1)O)F)OC RBRQDLJMXKZRJN-UHFFFAOYSA-N 0.000 description 3
- JRWKTSZPTRTXFS-UHFFFAOYSA-N 2-bromo-4-fluoro-5-methoxyaniline Chemical compound COC1=CC(N)=C(Br)C=C1F JRWKTSZPTRTXFS-UHFFFAOYSA-N 0.000 description 3
- GVVVJOVWEIZBJR-UHFFFAOYSA-N 2-methyl-1-(4-nitropyrazol-1-yl)propan-2-ol Chemical compound CC(C)(O)CN1C=C([N+]([O-])=O)C=N1 GVVVJOVWEIZBJR-UHFFFAOYSA-N 0.000 description 3
- BYHQTRFJOGIQAO-GOSISDBHSA-N 3-(4-bromophenyl)-8-[(2R)-2-hydroxypropyl]-1-[(3-methoxyphenyl)methyl]-1,3,8-triazaspiro[4.5]decan-2-one Chemical compound C[C@H](CN1CCC2(CC1)CN(C(=O)N2CC3=CC(=CC=C3)OC)C4=CC=C(C=C4)Br)O BYHQTRFJOGIQAO-GOSISDBHSA-N 0.000 description 3
- KGJIAMQQRPJQPI-UHFFFAOYSA-N 3-[5-[(2,4-dimethoxyphenyl)methylamino]-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl]-6-ethyl-1-[1-(2-hydroxy-2-methylpropyl)pyrazol-4-yl]piperidin-2-one Chemical compound COC1=C(CNC2=NC=3C=C(C(=CC=3C=3N2N=C(N=3)C2C(N(C(CC2)CC)C=2C=NN(C=2)CC(C)(C)O)=O)F)OC)C=CC(=C1)OC KGJIAMQQRPJQPI-UHFFFAOYSA-N 0.000 description 3
- BWNSMURLWRZECR-UHFFFAOYSA-N 3-[5-[(2,4-dimethoxyphenyl)methylamino]-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl]cyclohexan-1-ol Chemical compound C1=C(C(OC)=CC2=C1C1=NC(C3CC(O)CCC3)=NN1C(=N2)NCC1=C(OC)C=C(OC)C=C1)F BWNSMURLWRZECR-UHFFFAOYSA-N 0.000 description 3
- XLABCWKWDUKTMC-UHFFFAOYSA-N 3-[5-[(2,4-dimethoxyphenyl)methylamino]-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl]cyclohexan-1-one Chemical compound COC1=C(CNC2=NC=3C=C(C(=CC=3C=3N2N=C(N=3)C2CC(CCC2)=O)F)OC)C=CC(=C1)OC XLABCWKWDUKTMC-UHFFFAOYSA-N 0.000 description 3
- FZFWTUBJDMRESK-UHFFFAOYSA-N 4-bromo-1-(5,8-dioxaspiro[3.4]octan-2-yl)pyrazole Chemical compound BrC=1C=NN(C=1)C1CC2(C1)OCCO2 FZFWTUBJDMRESK-UHFFFAOYSA-N 0.000 description 3
- WRDSDCYKWVXMRY-UHFFFAOYSA-N 4-bromo-1-(oxan-4-yl)pyrazole Chemical compound C1=C(Br)C=NN1C1CCOCC1 WRDSDCYKWVXMRY-UHFFFAOYSA-N 0.000 description 3
- VORVZBFZCQOHQZ-UHFFFAOYSA-N 4-bromo-1-[(3-methyloxetan-3-yl)methyl]pyrazole Chemical compound C1=C(Br)C=NN1CC1(C)COC1 VORVZBFZCQOHQZ-UHFFFAOYSA-N 0.000 description 3
- DBNIOKFPWVOQPU-UHFFFAOYSA-N 4-bromo-3-methyl-1-tritylpyrazole Chemical compound C1=C(Br)C(C)=NN1C(C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 DBNIOKFPWVOQPU-UHFFFAOYSA-N 0.000 description 3
- ZQSJXZDXTSTMPB-UHFFFAOYSA-N 4-bromo-5-methyl-1-tritylpyrazole Chemical compound BrC=1C=NN(C=1C)C(C1=CC=CC=C1)(C1=CC=CC=C1)C1=CC=CC=C1 ZQSJXZDXTSTMPB-UHFFFAOYSA-N 0.000 description 3
- JVVRCYWZTJLJSG-UHFFFAOYSA-N 4-dimethylaminophenol Chemical compound CN(C)C1=CC=C(O)C=C1 JVVRCYWZTJLJSG-UHFFFAOYSA-N 0.000 description 3
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 3
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-dimethylaminopyridine Substances CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 3
- BPUPMHVBVYPFDZ-UHFFFAOYSA-N 5-methyl-1-[(2-methylpropan-2-yl)oxycarbonyl]piperidine-3-carboxylic acid Chemical compound CC1CC(C(O)=O)CN(C(=O)OC(C)(C)C)C1 BPUPMHVBVYPFDZ-UHFFFAOYSA-N 0.000 description 3
- CBDSIHCOUDRMMA-UHFFFAOYSA-N 5-methylpiperidine-3-carboxylic acid Chemical compound CC1CNCC(C(O)=O)C1 CBDSIHCOUDRMMA-UHFFFAOYSA-N 0.000 description 3
- CMSUPPMVATUSHX-UHFFFAOYSA-N 6-fluoro-8-methoxy-4-(1,2,4-triazol-1-yl)quinazolin-2-amine Chemical compound C1=C(C=C(C2=C1C(N1N=CN=C1)=NC(=N2)N)OC)F CMSUPPMVATUSHX-UHFFFAOYSA-N 0.000 description 3
- 229940127600 A2A receptor antagonist Drugs 0.000 description 3
- XWUBKQCTEDVXRS-UHFFFAOYSA-N BrC=1C(=NN(C=1)CC)COC1OCCCC1 Chemical compound BrC=1C(=NN(C=1)CC)COC1OCCCC1 XWUBKQCTEDVXRS-UHFFFAOYSA-N 0.000 description 3
- HWJYYSWQVWLQPV-UHFFFAOYSA-N C(#N)C1=C(C=C(C(=C1)F)OC(F)F)NC(OC)=O Chemical compound C(#N)C1=C(C=C(C(=C1)F)OC(F)F)NC(OC)=O HWJYYSWQVWLQPV-UHFFFAOYSA-N 0.000 description 3
- XXMNAPNYDWUVOJ-UHFFFAOYSA-N C(C)(C)(C)OC(=O)N1CC(CCC1)C1=NN2C(=NC=3C=C(C(=CC=3C2=N1)F)OC(F)F)NCC1=C(C=C(C=C1)OC)OC Chemical compound C(C)(C)(C)OC(=O)N1CC(CCC1)C1=NN2C(=NC=3C=C(C(=CC=3C2=N1)F)OC(F)F)NCC1=C(C=C(C=C1)OC)OC XXMNAPNYDWUVOJ-UHFFFAOYSA-N 0.000 description 3
- ZNWVZQLMDNLAIH-UHFFFAOYSA-N C(CN1N=C(C=C1)C1CC1)(O)(C)C Chemical compound C(CN1N=C(C=C1)C1CC1)(O)(C)C ZNWVZQLMDNLAIH-UHFFFAOYSA-N 0.000 description 3
- KAIVEBBCBSEEDY-UHFFFAOYSA-N C1(C)=NN(C=C1Br)CC1(OC2OCCCC2)CCC1 Chemical compound C1(C)=NN(C=C1Br)CC1(OC2OCCCC2)CCC1 KAIVEBBCBSEEDY-UHFFFAOYSA-N 0.000 description 3
- JNXIVOLVCKINMC-UHFFFAOYSA-N C1(CCC(C)N(C1)C1=CN(N=C1)C1CCC2(OCCO2)CC1)C(=O)NN Chemical compound C1(CCC(C)N(C1)C1=CN(N=C1)C1CCC2(OCCO2)CC1)C(=O)NN JNXIVOLVCKINMC-UHFFFAOYSA-N 0.000 description 3
- XGHZOTZODSXKNW-UHFFFAOYSA-N C12=CC(=CC(=C2N=C(N2C1=NC(C1CN(C(C)CC1)C=1C(C)=NN(C=1)CC(C)(C)O)=N2)NCC1=C(OC)C=C(OC)C=C1)OC)F Chemical compound C12=CC(=CC(=C2N=C(N2C1=NC(C1CN(C(C)CC1)C=1C(C)=NN(C=1)CC(C)(C)O)=N2)NCC1=C(OC)C=C(OC)C=C1)OC)F XGHZOTZODSXKNW-UHFFFAOYSA-N 0.000 description 3
- NODCFPOBUYHFJP-HXUWFJFHSA-N C1=C(C(=CC2=C1C1=NC(=NN1C(=N2)NCC1=C(OC)C=C(OC)C=C1)[C@@H]1CCCN(C1)C1=CN(N=C1C)CSC)OC)F Chemical compound C1=C(C(=CC2=C1C1=NC(=NN1C(=N2)NCC1=C(OC)C=C(OC)C=C1)[C@@H]1CCCN(C1)C1=CN(N=C1C)CSC)OC)F NODCFPOBUYHFJP-HXUWFJFHSA-N 0.000 description 3
- YLUWEFNPFJRMMQ-UHFFFAOYSA-N C1=C(C(=CC2=C1C1=NC(C3S(=O)(=O)CCN(C3)C3=CN(N=C3C)CC(O)(C)C)=NN1C(=N2)NCC1=C(OC)C=C(OC)C=C1)OC)F Chemical compound C1=C(C(=CC2=C1C1=NC(C3S(=O)(=O)CCN(C3)C3=CN(N=C3C)CC(O)(C)C)=NN1C(=N2)NCC1=C(OC)C=C(OC)C=C1)OC)F YLUWEFNPFJRMMQ-UHFFFAOYSA-N 0.000 description 3
- NBSJTKXNIOKNMA-GOSISDBHSA-N C1=C(C(=CC2=C1C1=NC([C@@H]3CCCN(C(=O)OC(C)(C)C)C3)=NN1C(=N2)NCC1=C(OC)C=C(OC)C=C1)OC)F Chemical compound C1=C(C(=CC2=C1C1=NC([C@@H]3CCCN(C(=O)OC(C)(C)C)C3)=NN1C(=N2)NCC1=C(OC)C=C(OC)C=C1)OC)F NBSJTKXNIOKNMA-GOSISDBHSA-N 0.000 description 3
- RHFLIXVIJLCBAA-CYBMUJFWSA-N C1=C(C(=CC2=C1C1=NC([C@@H]3CCCN(C4=CN(N=C4C)CS(=O)(=O)C)C3)=NN1C(=N2)N)OC)F Chemical compound C1=C(C(=CC2=C1C1=NC([C@@H]3CCCN(C4=CN(N=C4C)CS(=O)(=O)C)C3)=NN1C(=N2)N)OC)F RHFLIXVIJLCBAA-CYBMUJFWSA-N 0.000 description 3
- WTNYGGDNRYVTPM-QYWNIODHSA-N C1=C(C(=CC2=C1C1=NC([C@@H]3CCCN(C=4C=NN(C=4)C4CCC4(OC)OC)C3)=NN1C(=N2)NCC1=C(OC)C=C(OC)C=C1)OC)F Chemical compound C1=C(C(=CC2=C1C1=NC([C@@H]3CCCN(C=4C=NN(C=4)C4CCC4(OC)OC)C3)=NN1C(=N2)NCC1=C(OC)C=C(OC)C=C1)OC)F WTNYGGDNRYVTPM-QYWNIODHSA-N 0.000 description 3
- HDVFZJFUIVZMMQ-UHFFFAOYSA-N C1=C(C=C(C2=C1C1=NC(C3(CN(CCC3)C(=O)OCC3=CC=CC=C3)F)=NN1C(=N2)NCC1=CC=C(C=C1OC)OC)OC)F Chemical compound C1=C(C=C(C2=C1C1=NC(C3(CN(CCC3)C(=O)OCC3=CC=CC=C3)F)=NN1C(=N2)NCC1=CC=C(C=C1OC)OC)OC)F HDVFZJFUIVZMMQ-UHFFFAOYSA-N 0.000 description 3
- MXQBQWHUGUGSFT-UHFFFAOYSA-N C1=C(C=C(C2=C1C1=NC(C3(CN(CCC3)C=3C=NN(C=3)CC(O)(C)C)F)=NN1C(=N2)N)OC)F Chemical compound C1=C(C=C(C2=C1C1=NC(C3(CN(CCC3)C=3C=NN(C=3)CC(O)(C)C)F)=NN1C(=N2)N)OC)F MXQBQWHUGUGSFT-UHFFFAOYSA-N 0.000 description 3
- WVPIBCPHNGQKOJ-GOSISDBHSA-N C1=C(F)C=C(C2=C1C1=NC([C@@H]3CCCN(C3)C(=O)OC(C)(C)C)=NN1C(=N2)NCC1=CC=C(OC)C=C1OC)OC Chemical compound C1=C(F)C=C(C2=C1C1=NC([C@@H]3CCCN(C3)C(=O)OC(C)(C)C)=NN1C(=N2)NCC1=CC=C(OC)C=C1OC)OC WVPIBCPHNGQKOJ-GOSISDBHSA-N 0.000 description 3
- UVWGKUJIOCYTCQ-UHFFFAOYSA-N C=1C(=CN(N=1)C1CC(=O)C1)Br Chemical compound C=1C(=CN(N=1)C1CC(=O)C1)Br UVWGKUJIOCYTCQ-UHFFFAOYSA-N 0.000 description 3
- VRNGWJLKJMZXLK-UHFFFAOYSA-N C=1C(=CN(N=1)C1CCC1(OC)OC)Br Chemical compound C=1C(=CN(N=1)C1CCC1(OC)OC)Br VRNGWJLKJMZXLK-UHFFFAOYSA-N 0.000 description 3
- PPALJANFDIDXDN-UHFFFAOYSA-N CC(C)(CO)n1cc(cn1)[N+]([O-])=O Chemical compound CC(C)(CO)n1cc(cn1)[N+]([O-])=O PPALJANFDIDXDN-UHFFFAOYSA-N 0.000 description 3
- PCRXOWPBRLTCQQ-OAHLLOKOSA-N COC1=C(CNC2=NC=3C(=CC(=CC=3C=3N2N=C(N=3)[C@H]2CNCCC2)F)OC)C=CC(=C1)OC Chemical compound COC1=C(CNC2=NC=3C(=CC(=CC=3C=3N2N=C(N=3)[C@H]2CNCCC2)F)OC)C=CC(=C1)OC PCRXOWPBRLTCQQ-OAHLLOKOSA-N 0.000 description 3
- NZHAZDBTNXQLRI-UHFFFAOYSA-N COC1=C(CNC2=NC=3C=C(C(=CC=3C=3N2N=C(N=3)C2C(N(CCC2)C=2C=NN(C=2)CC(C)(C)O)=O)F)OC)C=CC(=C1)OC Chemical compound COC1=C(CNC2=NC=3C=C(C(=CC=3C=3N2N=C(N=3)C2C(N(CCC2)C=2C=NN(C=2)CC(C)(C)O)=O)F)OC)C=CC(=C1)OC NZHAZDBTNXQLRI-UHFFFAOYSA-N 0.000 description 3
- CFBHAOWMGVTRHS-UHFFFAOYSA-N COC1=C(CNC2=NC=3C=C(C(=CC=3C=3N2N=C(N=3)C2CN(CCS2(=O)=O)C=2C=NN(C=2C)CC(C)(C)O)F)OC)C=CC(=C1)OC Chemical compound COC1=C(CNC2=NC=3C=C(C(=CC=3C=3N2N=C(N=3)C2CN(CCS2(=O)=O)C=2C=NN(C=2C)CC(C)(C)O)F)OC)C=CC(=C1)OC CFBHAOWMGVTRHS-UHFFFAOYSA-N 0.000 description 3
- RXEQNDRQPIFZNO-MGBGTMOVSA-N COC1=C(CNC2=NC=3C=C(C(=CC=3C=3N2N=C(N=3)[C@H]2CN(CCC2)C=2C(=NN(C=2)C(C2=CC=CC=C2)(C2=CC=CC=C2)C2=CC=CC=C2)C)F)OC)C=CC(=C1)OC Chemical compound COC1=C(CNC2=NC=3C=C(C(=CC=3C=3N2N=C(N=3)[C@H]2CN(CCC2)C=2C(=NN(C=2)C(C2=CC=CC=C2)(C2=CC=CC=C2)C2=CC=CC=C2)C)F)OC)C=CC(=C1)OC RXEQNDRQPIFZNO-MGBGTMOVSA-N 0.000 description 3
- MMAAVCCNNWZHGE-JOCHJYFZSA-N COC1=C(CNC2=NC=3C=C(C(=CC=3C=3N2N=C(N=3)[C@H]2CN(CCC2)C=2C=NN(C=2)CCCC(C)=O)F)OC)C=CC(=C1)OC Chemical compound COC1=C(CNC2=NC=3C=C(C(=CC=3C=3N2N=C(N=3)[C@H]2CN(CCC2)C=2C=NN(C=2)CCCC(C)=O)F)OC)C=CC(=C1)OC MMAAVCCNNWZHGE-JOCHJYFZSA-N 0.000 description 3
- NAODVROXJQEZNU-HXUWFJFHSA-N COC1=C(CNC2=NC=3C=C(C(=CC=3C=3N2N=C(N=3)[C@H]2CN(CCC2)C=2C=NN(C=2C)CSC)F)OC)C=CC(=C1)OC Chemical compound COC1=C(CNC2=NC=3C=C(C(=CC=3C=3N2N=C(N=3)[C@H]2CN(CCC2)C=2C=NN(C=2C)CSC)F)OC)C=CC(=C1)OC NAODVROXJQEZNU-HXUWFJFHSA-N 0.000 description 3
- QNGVFALLKMVMTO-UHFFFAOYSA-N COC1=C(F)C=C2C3=NC(=NN3C(N)=NC2=C1)C12CC1CN(C2)C1=CN(CC2(O)CCC2)N=C1 Chemical compound COC1=C(F)C=C2C3=NC(=NN3C(N)=NC2=C1)C12CC1CN(C2)C1=CN(CC2(O)CCC2)N=C1 QNGVFALLKMVMTO-UHFFFAOYSA-N 0.000 description 3
- HCEPPMLPPODGGW-UHFFFAOYSA-N COC1=CC2=C(C=C1F)C1=NC(=NN1C(N)=N2)C1CCC(C)N(C1)C1=CN(CC2(O)CCC2)N=C1 Chemical compound COC1=CC2=C(C=C1F)C1=NC(=NN1C(N)=N2)C1CCC(C)N(C1)C1=CN(CC2(O)CCC2)N=C1 HCEPPMLPPODGGW-UHFFFAOYSA-N 0.000 description 3
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 3
- 241000701022 Cytomegalovirus Species 0.000 description 3
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 3
- BUDQDWGNQVEFAC-UHFFFAOYSA-N Dihydropyran Chemical compound C1COC=CC1 BUDQDWGNQVEFAC-UHFFFAOYSA-N 0.000 description 3
- LETJXBPMANOHER-CQSZACIVSA-N FC(OC=1C(=CC=2C=3N(C(=NC=2C=1)NCC1=C(C=C(C=C1)OC)OC)N=C(N=3)[C@H]1CNCCC1)F)F Chemical compound FC(OC=1C(=CC=2C=3N(C(=NC=2C=1)NCC1=C(C=C(C=C1)OC)OC)N=C(N=3)[C@H]1CNCCC1)F)F LETJXBPMANOHER-CQSZACIVSA-N 0.000 description 3
- XDRWMNDQTGOXKF-UHFFFAOYSA-N FC1(CN(CCC1)C(=O)OCC1=CC=CC=C1)C(=O)NN Chemical compound FC1(CN(CCC1)C(=O)OCC1=CC=CC=C1)C(=O)NN XDRWMNDQTGOXKF-UHFFFAOYSA-N 0.000 description 3
- CXVSQDLWMPSQMR-CYBMUJFWSA-N FC1=CC=2C=3N(C(=NC=2C=C1OC)N)N=C(N=3)[C@H]1CN(CCC1)C=1C=NN(C=1C)CS(=O)(=O)C Chemical compound FC1=CC=2C=3N(C(=NC=2C=C1OC)N)N=C(N=3)[C@H]1CN(CCC1)C=1C=NN(C=1C)CS(=O)(=O)C CXVSQDLWMPSQMR-CYBMUJFWSA-N 0.000 description 3
- 241000711549 Hepacivirus C Species 0.000 description 3
- 241000725303 Human immunodeficiency virus Species 0.000 description 3
- 206010021143 Hypoxia Diseases 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- XHUGNCIRTJIVJA-UHFFFAOYSA-N NC1=NC=2C=C(C(=CC=2C=2N1N=C(N=2)C1C(N(CCC1)C=1C=NN(C=1)CC(C)(C)O)=O)F)OC Chemical compound NC1=NC=2C=C(C(=CC=2C=2N1N=C(N=2)C1C(N(CCC1)C=1C=NN(C=1)CC(C)(C)O)=O)F)OC XHUGNCIRTJIVJA-UHFFFAOYSA-N 0.000 description 3
- 208000012902 Nervous system disease Diseases 0.000 description 3
- KIDBCXKFCAFVPL-UONOGXRCSA-N O(C)C1=C(C=C2C3=NC([C@@H]4CC[C@@H](N(C4)C=4C=NN(C=4)CC(C)(C)O)C)=NN3C(=NC2=C1)N)F Chemical compound O(C)C1=C(C=C2C3=NC([C@@H]4CC[C@@H](N(C4)C=4C=NN(C=4)CC(C)(C)O)C)=NN3C(=NC2=C1)N)F KIDBCXKFCAFVPL-UONOGXRCSA-N 0.000 description 3
- HPWSSIOBVVQDKT-PZJWPPBQSA-N O(C)C1=C(C=C2C3=NC([C@@H]4CC[C@@H](N(C4)C=4C=NN(C=4)CC(C)(C)O)C)=NN3C(=NC2=C1)NCC1=CC=C(OC)C=C1OC)F Chemical compound O(C)C1=C(C=C2C3=NC([C@@H]4CC[C@@H](N(C4)C=4C=NN(C=4)CC(C)(C)O)C)=NN3C(=NC2=C1)NCC1=CC=C(OC)C=C1OC)F HPWSSIOBVVQDKT-PZJWPPBQSA-N 0.000 description 3
- 101100272976 Panax ginseng CYP716A53v2 gene Proteins 0.000 description 3
- 208000018737 Parkinson disease Diseases 0.000 description 3
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- KZKXTCFXVBOVCQ-UHFFFAOYSA-N [1-(oxan-2-yloxy)cyclobutyl]methyl methanesulfonate Chemical compound CS(=O)(=O)OCC1(CCC1)OC1OCCCC1 KZKXTCFXVBOVCQ-UHFFFAOYSA-N 0.000 description 3
- 230000004913 activation Effects 0.000 description 3
- 150000001413 amino acids Chemical group 0.000 description 3
- 230000033115 angiogenesis Effects 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 239000012455 biphasic mixture Substances 0.000 description 3
- 210000003169 central nervous system Anatomy 0.000 description 3
- 238000004587 chromatography analysis Methods 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000005859 coupling reaction Methods 0.000 description 3
- 239000006071 cream Substances 0.000 description 3
- VUSWCWPCANWBFG-UHFFFAOYSA-M cyclohex-3-ene-1-carboxylate Chemical compound [O-]C(=O)C1CCC=CC1 VUSWCWPCANWBFG-UHFFFAOYSA-M 0.000 description 3
- NZNMSOFKMUBTKW-UHFFFAOYSA-N cyclohexanecarboxylic acid Chemical compound OC(=O)C1CCCCC1 NZNMSOFKMUBTKW-UHFFFAOYSA-N 0.000 description 3
- XUWHAWMETYGRKB-UHFFFAOYSA-N delta-valerolactam Natural products O=C1CCCCN1 XUWHAWMETYGRKB-UHFFFAOYSA-N 0.000 description 3
- 229910052805 deuterium Inorganic materials 0.000 description 3
- KTWIAHPYXZOHPQ-UHFFFAOYSA-N diethyl 2-[3-[[1-(2-hydroxy-2-methylpropyl)pyrazol-4-yl]amino]pentyl]propanedioate Chemical compound OC(CN1N=CC(=C1)NC(CCC(C(=O)OCC)C(=O)OCC)CC)(C)C KTWIAHPYXZOHPQ-UHFFFAOYSA-N 0.000 description 3
- 239000000839 emulsion Substances 0.000 description 3
- SRZCNFCBCVDIHX-UHFFFAOYSA-N ethyl 2-methyl-2-(4-nitropyrazol-1-yl)propanoate Chemical compound CCOC(=O)C(C)(C)N1C=C([N+]([O-])=O)C=N1 SRZCNFCBCVDIHX-UHFFFAOYSA-N 0.000 description 3
- ZPERJCOYWLFHSS-UHFFFAOYSA-N ethyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-ene-1-carboxylate Chemical compound C1C(C(=O)OCC)CCC=C1B1OC(C)(C)C(C)(C)O1 ZPERJCOYWLFHSS-UHFFFAOYSA-N 0.000 description 3
- UOWFQCBJBIWAGS-UHFFFAOYSA-N ethyl 3-(trifluoromethylsulfonyloxy)cyclohex-3-ene-1-carboxylate Chemical compound CCOC(=O)C1CCC=C(C1)OS(=O)(=O)C(F)(F)F UOWFQCBJBIWAGS-UHFFFAOYSA-N 0.000 description 3
- QVOQLAPRZZXPDF-UHFFFAOYSA-N ethyl 6-ethyl-1-[1-(2-hydroxy-2-methylpropyl)pyrazol-4-yl]-2-oxopiperidine-3-carboxylate Chemical compound C(C)C1CCC(C(N1C=1C=NN(C=1)CC(C)(C)O)=O)C(=O)OCC QVOQLAPRZZXPDF-UHFFFAOYSA-N 0.000 description 3
- 230000006870 function Effects 0.000 description 3
- 102000037865 fusion proteins Human genes 0.000 description 3
- 108020001507 fusion proteins Proteins 0.000 description 3
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 3
- RCCPEORTSYDPMB-UHFFFAOYSA-N hydroxy benzenecarboximidothioate Chemical compound OSC(=N)C1=CC=CC=C1 RCCPEORTSYDPMB-UHFFFAOYSA-N 0.000 description 3
- 230000007954 hypoxia Effects 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 210000002865 immune cell Anatomy 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 239000004615 ingredient Substances 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 238000007918 intramuscular administration Methods 0.000 description 3
- 230000000155 isotopic effect Effects 0.000 description 3
- 210000003734 kidney Anatomy 0.000 description 3
- 239000003446 ligand Substances 0.000 description 3
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 3
- DFGPYKOGYUDPRB-UHFFFAOYSA-N methyl 2-(4-bromopyrazol-1-yl)-2-methylpropanoate Chemical compound COC(=O)C(C)(C)N1C=C(Br)C=N1 DFGPYKOGYUDPRB-UHFFFAOYSA-N 0.000 description 3
- GHKLNDDTNVEOEC-UHFFFAOYSA-N methyl 4-methyl-2-methylidene-5-oxopentanoate Chemical compound COC(=O)C(=C)CC(C)C=O GHKLNDDTNVEOEC-UHFFFAOYSA-N 0.000 description 3
- 210000000066 myeloid cell Anatomy 0.000 description 3
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 3
- 230000009826 neoplastic cell growth Effects 0.000 description 3
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 230000001737 promoting effect Effects 0.000 description 3
- 125000003373 pyrazinyl group Chemical group 0.000 description 3
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical group O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 3
- 125000000168 pyrrolyl group Chemical group 0.000 description 3
- 125000004260 quinazolin-2-yl group Chemical group [H]C1=NC(*)=NC2=C1C([H])=C([H])C([H])=C2[H] 0.000 description 3
- 238000001959 radiotherapy Methods 0.000 description 3
- 210000003289 regulatory T cell Anatomy 0.000 description 3
- 230000001105 regulatory effect Effects 0.000 description 3
- 230000019491 signal transduction Effects 0.000 description 3
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- 125000001544 thienyl group Chemical group 0.000 description 3
- 210000001519 tissue Anatomy 0.000 description 3
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 3
- 230000004614 tumor growth Effects 0.000 description 3
- RLCXFBTZYLRHPH-MRVPVSSYSA-N (3R)-1-(1-methylpyrazol-4-yl)piperidine-3-carbohydrazide Chemical compound CN1N=CC(=C1)N1C[C@@H](CCC1)C(=O)NN RLCXFBTZYLRHPH-MRVPVSSYSA-N 0.000 description 2
- RDUPLTHSWXYTCM-WDEREUQCSA-N (3R,6S)-1-[1-(2-hydroxy-2-methylpropyl)pyrazol-4-yl]-6-methylpiperidine-3-carbohydrazide Chemical compound OC(CN1N=CC(=C1)N1C[C@@H](CC[C@@H]1C)C(=O)NN)(C)C RDUPLTHSWXYTCM-WDEREUQCSA-N 0.000 description 2
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 description 2
- MOWXJLUYGFNTAL-DEOSSOPVSA-N (s)-[2-chloro-4-fluoro-5-(7-morpholin-4-ylquinazolin-4-yl)phenyl]-(6-methoxypyridazin-3-yl)methanol Chemical compound N1=NC(OC)=CC=C1[C@@H](O)C1=CC(C=2C3=CC=C(C=C3N=CN=2)N2CCOCC2)=C(F)C=C1Cl MOWXJLUYGFNTAL-DEOSSOPVSA-N 0.000 description 2
- 125000004514 1,2,4-thiadiazolyl group Chemical group 0.000 description 2
- 125000004530 1,2,4-triazinyl group Chemical group N1=NC(=NC=C1)* 0.000 description 2
- NPQKISWLDHUTRY-UHFFFAOYSA-N 1-(1,4-dioxaspiro[4.5]decan-8-yl)-4-nitropyrazole Chemical compound [O-][N+](=O)C1=CN(N=C1)C1CCC2(CC1)OCCO2 NPQKISWLDHUTRY-UHFFFAOYSA-N 0.000 description 2
- XWZSKRHHQVCOPZ-UHFFFAOYSA-N 1-(4-amino-5-methylpyrazol-1-yl)-2-methylpropan-2-ol Chemical compound CC1=C(N)C=NN1CC(C)(C)O XWZSKRHHQVCOPZ-UHFFFAOYSA-N 0.000 description 2
- CBINSQKVJOQYCO-UHFFFAOYSA-N 1-(4-bromopyrazol-1-yl)-2-methylbutan-2-ol Chemical compound CCC(C)(O)Cn1cc(Br)cn1 CBINSQKVJOQYCO-UHFFFAOYSA-N 0.000 description 2
- HDLWLDXVEAXTMM-UHFFFAOYSA-N 1-(isocyanatomethyl)-2,4-dimethoxybenzene Chemical compound COC1=CC=C(CN=C=O)C(OC)=C1 HDLWLDXVEAXTMM-UHFFFAOYSA-N 0.000 description 2
- JLIDVCMBCGBIEY-UHFFFAOYSA-N 1-penten-3-one Chemical compound CCC(=O)C=C JLIDVCMBCGBIEY-UHFFFAOYSA-N 0.000 description 2
- GELKGHVAFRCJNA-UHFFFAOYSA-N 2,2-Dimethyloxirane Chemical compound CC1(C)CO1 GELKGHVAFRCJNA-UHFFFAOYSA-N 0.000 description 2
- KKMQAPFPCZZKBZ-CYBMUJFWSA-N 2-[4-[(3R)-3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidin-1-yl]pyrazol-1-yl]-2-methylpropan-1-ol Chemical compound NC1=NC=2C=C(C(=CC=2C=2N1N=C(N=2)[C@H]1CN(CCC1)C=1C=NN(C=1)C(CO)(C)C)F)OC KKMQAPFPCZZKBZ-CYBMUJFWSA-N 0.000 description 2
- UPNQYQVHMKNYDU-UHFFFAOYSA-N 2-amino-4-chloro-5-fluorobenzonitrile Chemical compound NC1=CC(Cl)=C(F)C=C1C#N UPNQYQVHMKNYDU-UHFFFAOYSA-N 0.000 description 2
- BMBFDDUUZGZXPR-UHFFFAOYSA-N 3-(4-bromopyrazol-1-yl)-2-methylbutan-2-ol Chemical compound BrC=1C=NN(C=1)C(C(C)(O)C)C BMBFDDUUZGZXPR-UHFFFAOYSA-N 0.000 description 2
- WYYOHSCLLIJWQD-UHFFFAOYSA-N 3-hydroxycyclohexane-1-carbohydrazide Chemical compound NNC(=O)C1CCCC(O)C1 WYYOHSCLLIJWQD-UHFFFAOYSA-N 0.000 description 2
- QOKKZKWWDAOPBQ-UHFFFAOYSA-N 4-(4-bromopyrazol-1-yl)-2-methylbutan-2-ol Chemical compound CC(C)(O)CCN1C=C(Br)C=N1 QOKKZKWWDAOPBQ-UHFFFAOYSA-N 0.000 description 2
- KVCQTKNUUQOELD-UHFFFAOYSA-N 4-amino-n-[1-(3-chloro-2-fluoroanilino)-6-methylisoquinolin-5-yl]thieno[3,2-d]pyrimidine-7-carboxamide Chemical compound N=1C=CC2=C(NC(=O)C=3C4=NC=NC(N)=C4SC=3)C(C)=CC=C2C=1NC1=CC=CC(Cl)=C1F KVCQTKNUUQOELD-UHFFFAOYSA-N 0.000 description 2
- FVRZLCWMJQIHOH-UHFFFAOYSA-N 4-bromo-3-(difluoromethyl)-1-(oxan-4-yl)pyrazole Chemical compound BrC=1C(=NN(C=1)C1CCOCC1)C(F)F FVRZLCWMJQIHOH-UHFFFAOYSA-N 0.000 description 2
- HWYWVZDJOQXJHH-UHFFFAOYSA-N 4-bromo-5-(difluoromethyl)-1h-pyrazole Chemical compound FC(F)C=1NN=CC=1Br HWYWVZDJOQXJHH-UHFFFAOYSA-N 0.000 description 2
- IXQPRETWBGVNPJ-UHFFFAOYSA-N 4-bromo-5-methyl-1h-pyrazole Chemical compound CC=1NN=CC=1Br IXQPRETWBGVNPJ-UHFFFAOYSA-N 0.000 description 2
- IBSJUWVEKZEVNN-UHFFFAOYSA-N 4-nitro-1-[[1-(oxan-2-yloxy)cyclopropyl]methyl]pyrazole Chemical compound C1=C([N+](=O)[O-])C=NN1CC1(OC2OCCCC2)CC1 IBSJUWVEKZEVNN-UHFFFAOYSA-N 0.000 description 2
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
- NSPMIYGKQJPBQR-UHFFFAOYSA-N 4H-1,2,4-triazole Chemical compound C=1N=CNN=1 NSPMIYGKQJPBQR-UHFFFAOYSA-N 0.000 description 2
- KCBWAFJCKVKYHO-UHFFFAOYSA-N 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-[[4-[1-propan-2-yl-4-(trifluoromethyl)imidazol-2-yl]phenyl]methyl]pyrazolo[3,4-d]pyrimidine Chemical compound C1(CC1)C1=NC=NC(=C1C1=NC=C2C(=N1)N(N=C2)CC1=CC=C(C=C1)C=1N(C=C(N=1)C(F)(F)F)C(C)C)OC KCBWAFJCKVKYHO-UHFFFAOYSA-N 0.000 description 2
- STQGQHZAVUOBTE-UHFFFAOYSA-N 7-Cyan-hept-2t-en-4,6-diinsaeure Natural products C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(C)=O)CC1OC1CC(N)C(O)C(C)O1 STQGQHZAVUOBTE-UHFFFAOYSA-N 0.000 description 2
- ZKHQWZAMYRWXGA-UHFFFAOYSA-N Adenosine triphosphate Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(=O)OP(O)(=O)OP(O)(O)=O)C(O)C1O ZKHQWZAMYRWXGA-UHFFFAOYSA-N 0.000 description 2
- 208000024827 Alzheimer disease Diseases 0.000 description 2
- 208000035143 Bacterial infection Diseases 0.000 description 2
- SYIJIKAVKFYHLT-UHFFFAOYSA-N BrC=1C(=NN(C=1)C(C(C)=O)(C)C)C Chemical compound BrC=1C(=NN(C=1)C(C(C)=O)(C)C)C SYIJIKAVKFYHLT-UHFFFAOYSA-N 0.000 description 2
- AXOIDZXPZOAYMQ-UHFFFAOYSA-N BrC=1C=NN(C=1)C(COC1OCCCC1)(C)C Chemical compound BrC=1C=NN(C=1)C(COC1OCCCC1)(C)C AXOIDZXPZOAYMQ-UHFFFAOYSA-N 0.000 description 2
- HBUWLXXZWMKMKM-UHFFFAOYSA-N BrC=1C=NN(C=1C(F)F)C1CCOCC1 Chemical compound BrC=1C=NN(C=1C(F)F)C1CCOCC1 HBUWLXXZWMKMKM-UHFFFAOYSA-N 0.000 description 2
- DVMHQMMLFPDDLU-SNVBAGLBSA-N C(C)(C)(C)OC(=O)N1C[C@@H](CCC1)C1=NN2C(=NC=3C=C(C(=CC=3C2=N1)F)OC(F)F)O Chemical compound C(C)(C)(C)OC(=O)N1C[C@@H](CCC1)C1=NN2C(=NC=3C=C(C(=CC=3C2=N1)F)OC(F)F)O DVMHQMMLFPDDLU-SNVBAGLBSA-N 0.000 description 2
- IMMVVBBWSCLWMP-UHFFFAOYSA-N C(C)C1N(C(=O)C(C(=O)NN)CC1)C=1C=NN(C=1)CC(C)(C)O Chemical compound C(C)C1N(C(=O)C(C(=O)NN)CC1)C=1C=NN(C=1)CC(C)(C)O IMMVVBBWSCLWMP-UHFFFAOYSA-N 0.000 description 2
- 102100036842 C-C motif chemokine 19 Human genes 0.000 description 2
- 102100036846 C-C motif chemokine 21 Human genes 0.000 description 2
- IXSGQFWMOGWRAX-UHFFFAOYSA-N C1(=C(C=NN1CC1(OC2OCCCC2)CCC1)Br)C Chemical compound C1(=C(C=NN1CC1(OC2OCCCC2)CCC1)Br)C IXSGQFWMOGWRAX-UHFFFAOYSA-N 0.000 description 2
- PLKOANDRSGFJMR-UHFFFAOYSA-N C1=C(C(OC)=CC2=C1C1=NC(=NN1C(=N2)NCC1=C(OC)C=C(OC)C=C1)C1CCCC(O)(C=2C=NN(C=2)CC)C1)F Chemical compound C1=C(C(OC)=CC2=C1C1=NC(=NN1C(=N2)NCC1=C(OC)C=C(OC)C=C1)C1CCCC(O)(C=2C=NN(C=2)CC)C1)F PLKOANDRSGFJMR-UHFFFAOYSA-N 0.000 description 2
- IPVXZIMZMXVEMX-UHFFFAOYSA-N C1CC(C)N(CC1C(=O)NN)C=1C(C)=NN(C=1)CC(O)(C)C Chemical compound C1CC(C)N(CC1C(=O)NN)C=1C(C)=NN(C=1)CC(O)(C)C IPVXZIMZMXVEMX-UHFFFAOYSA-N 0.000 description 2
- KLMWEZHEZIGKTB-UHFFFAOYSA-N C=1(C(=CN(N=1)C(C(C)O)(C)C)Br)C Chemical compound C=1(C(=CN(N=1)C(C(C)O)(C)C)Br)C KLMWEZHEZIGKTB-UHFFFAOYSA-N 0.000 description 2
- RXFDMGWBWLHJFL-UHFFFAOYSA-N CC(C(C)O)(C)N1N=CC(=C1)[N+](=O)[O-] Chemical compound CC(C(C)O)(C)N1N=CC(=C1)[N+](=O)[O-] RXFDMGWBWLHJFL-UHFFFAOYSA-N 0.000 description 2
- QTDUVDGURQDJEX-UHFFFAOYSA-N CC1(COC(OC1)C1=CC=CC=C1)CN1N=CC(=C1)[N+](=O)[O-] Chemical compound CC1(COC(OC1)C1=CC=CC=C1)CN1N=CC(=C1)[N+](=O)[O-] QTDUVDGURQDJEX-UHFFFAOYSA-N 0.000 description 2
- TVVYCQXKIMRSRW-UHFFFAOYSA-N COC1=C(CN=C=NC2=C(C#N)C=C(C=C2F)F)C=CC(=C1)OC Chemical compound COC1=C(CN=C=NC2=C(C#N)C=C(C=C2F)F)C=CC(=C1)OC TVVYCQXKIMRSRW-UHFFFAOYSA-N 0.000 description 2
- VRVHWMBQCSJRBF-MGBGTMOVSA-N COC1=C(CNC2=NC=3C=C(C(=CC=3C=3N2N=C(N=3)[C@H]2CN(CCC2)C=2C=NN(C=2C)C(C2=CC=CC=C2)(C2=CC=CC=C2)C2=CC=CC=C2)F)OC)C=CC(=C1)OC Chemical compound COC1=C(CNC2=NC=3C=C(C(=CC=3C=3N2N=C(N=3)[C@H]2CN(CCC2)C=2C=NN(C=2C)C(C2=CC=CC=C2)(C2=CC=CC=C2)C2=CC=CC=C2)F)OC)C=CC(=C1)OC VRVHWMBQCSJRBF-MGBGTMOVSA-N 0.000 description 2
- NMHKBAWEMIHTMM-UHFFFAOYSA-N COC1=C2N=C(N)N3N=C(N=C3C2=CC=C1)C1CCCC(O)(C1)C1=CN(CC(C)(C)O)N=C1 Chemical compound COC1=C2N=C(N)N3N=C(N=C3C2=CC=C1)C1CCCC(O)(C1)C1=CN(CC(C)(C)O)N=C1 NMHKBAWEMIHTMM-UHFFFAOYSA-N 0.000 description 2
- WDANRYHLOXSCOE-LSDHHAIUSA-N COC1=CC2=C(C=C1F)C1=NC(=NN1C(N)=N2)[C@@H]1CCCN(C1)C1=CN(CCC[C@H](C)O)N=C1 Chemical compound COC1=CC2=C(C=C1F)C1=NC(=NN1C(N)=N2)[C@@H]1CCCN(C1)C1=CN(CCC[C@H](C)O)N=C1 WDANRYHLOXSCOE-LSDHHAIUSA-N 0.000 description 2
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- XZMCDFZZKTWFGF-UHFFFAOYSA-N Cyanamide Chemical compound NC#N XZMCDFZZKTWFGF-UHFFFAOYSA-N 0.000 description 2
- HMFHBZSHGGEWLO-SOOFDHNKSA-N D-ribofuranose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H]1O HMFHBZSHGGEWLO-SOOFDHNKSA-N 0.000 description 2
- 108020004414 DNA Proteins 0.000 description 2
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 2
- 101000713085 Homo sapiens C-C motif chemokine 21 Proteins 0.000 description 2
- 241000701044 Human gammaherpesvirus 4 Species 0.000 description 2
- 241000701806 Human papillomavirus Species 0.000 description 2
- XDXDZDZNSLXDNA-TZNDIEGXSA-N Idarubicin Chemical compound C1[C@H](N)[C@H](O)[C@H](C)O[C@H]1O[C@@H]1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2C[C@@](O)(C(C)=O)C1 XDXDZDZNSLXDNA-TZNDIEGXSA-N 0.000 description 2
- XDXDZDZNSLXDNA-UHFFFAOYSA-N Idarubicin Natural products C1C(N)C(O)C(C)OC1OC1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2CC(O)(C(C)=O)C1 XDXDZDZNSLXDNA-UHFFFAOYSA-N 0.000 description 2
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 2
- 206010025323 Lymphomas Diseases 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical class CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 2
- 208000016285 Movement disease Diseases 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- AYCPARAPKDAOEN-LJQANCHMSA-N N-[(1S)-2-(dimethylamino)-1-phenylethyl]-6,6-dimethyl-3-[(2-methyl-4-thieno[3,2-d]pyrimidinyl)amino]-1,4-dihydropyrrolo[3,4-c]pyrazole-5-carboxamide Chemical compound C1([C@H](NC(=O)N2C(C=3NN=C(NC=4C=5SC=CC=5N=C(C)N=4)C=3C2)(C)C)CN(C)C)=CC=CC=C1 AYCPARAPKDAOEN-LJQANCHMSA-N 0.000 description 2
- FBONFPATKKLDMI-UHFFFAOYSA-N N-[(2,4-dimethoxyphenyl)methyl]-9-fluoro-8-methoxy-2-(5-methylpiperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine Chemical compound C1=C(C(=CC2=C1C1=NC(C3CC(CNC3)C)=NN1C(=N2)NCC1=C(OC)C=C(OC)C=C1)OC)F FBONFPATKKLDMI-UHFFFAOYSA-N 0.000 description 2
- ZPPZAYVJWZTMDW-UHFFFAOYSA-N N1CC(CCCC1)C1=NN2C(=NC=3C=C(C(=CC=3C2=N1)F)OC)NCC1=C(C=C(C=C1)OC)OC Chemical compound N1CC(CCCC1)C1=NN2C(=NC=3C=C(C(=CC=3C2=N1)F)OC)NCC1=C(C=C(C=C1)OC)OC ZPPZAYVJWZTMDW-UHFFFAOYSA-N 0.000 description 2
- OTTBRZRUGWBVOV-GOSISDBHSA-N NC1=NC=2C=C(C(=CC=2C=2N1N=C(N=2)[C@@H]1OCCN(C1)C=1C=NN(C=1C)CC(C)(O)C)F)OC Chemical compound NC1=NC=2C=C(C(=CC=2C=2N1N=C(N=2)[C@@H]1OCCN(C1)C=1C=NN(C=1C)CC(C)(O)C)F)OC OTTBRZRUGWBVOV-GOSISDBHSA-N 0.000 description 2
- FPPUUYLOODFWBH-GFCCVEGCSA-N NC1=NC=2C=C(C(=CC=2C=2N1N=C(N=2)[C@H]1CN(CCC1)C1=NN(C=N1)CC(C)(O)C)F)OC Chemical compound NC1=NC=2C=C(C(=CC=2C=2N1N=C(N=2)[C@H]1CN(CCC1)C1=NN(C=N1)CC(C)(O)C)F)OC FPPUUYLOODFWBH-GFCCVEGCSA-N 0.000 description 2
- MVWFRIHQMRTEFY-UHFFFAOYSA-N NC=1C=NN(C=1)C(C(C)O)(C)C Chemical compound NC=1C=NN(C=1)C(C(C)O)(C)C MVWFRIHQMRTEFY-UHFFFAOYSA-N 0.000 description 2
- 208000025966 Neurological disease Diseases 0.000 description 2
- BYIVOKKPJXTLCK-NWDGAFQWSA-N OC(CN1N=CC(=C1)N1C[C@@H](CC[C@@H]1C)C(=O)OC)(C)C Chemical compound OC(CN1N=CC(=C1)N1C[C@@H](CC[C@@H]1C)C(=O)OC)(C)C BYIVOKKPJXTLCK-NWDGAFQWSA-N 0.000 description 2
- BYIVOKKPJXTLCK-NEPJUHHUSA-N OC(CN1N=CC(=C1)N1C[C@H](CC[C@H]1C)C(=O)OC)(C)C Chemical compound OC(CN1N=CC(=C1)N1C[C@H](CC[C@H]1C)C(=O)OC)(C)C BYIVOKKPJXTLCK-NEPJUHHUSA-N 0.000 description 2
- 239000012270 PD-1 inhibitor Substances 0.000 description 2
- 239000012668 PD-1-inhibitor Substances 0.000 description 2
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- NBBJYMSMWIIQGU-UHFFFAOYSA-N Propionic aldehyde Chemical compound CCC=O NBBJYMSMWIIQGU-UHFFFAOYSA-N 0.000 description 2
- 102100030086 Receptor tyrosine-protein kinase erbB-2 Human genes 0.000 description 2
- 229940124639 Selective inhibitor Drugs 0.000 description 2
- 206010041067 Small cell lung cancer Diseases 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
- NKANXQFJJICGDU-QPLCGJKRSA-N Tamoxifen Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 NKANXQFJJICGDU-QPLCGJKRSA-N 0.000 description 2
- MUMGGOZAMZWBJJ-DYKIIFRCSA-N Testostosterone Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 MUMGGOZAMZWBJJ-DYKIIFRCSA-N 0.000 description 2
- 241000534944 Thia Species 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 2
- 108010073929 Vascular Endothelial Growth Factor A Proteins 0.000 description 2
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 description 2
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 description 2
- LXRZVMYMQHNYJB-UNXOBOICSA-N [(1R,2S,4R)-4-[[5-[4-[(1R)-7-chloro-1,2,3,4-tetrahydroisoquinolin-1-yl]-5-methylthiophene-2-carbonyl]pyrimidin-4-yl]amino]-2-hydroxycyclopentyl]methyl sulfamate Chemical compound CC1=C(C=C(S1)C(=O)C1=C(N[C@H]2C[C@H](O)[C@@H](COS(N)(=O)=O)C2)N=CN=C1)[C@@H]1NCCC2=C1C=C(Cl)C=C2 LXRZVMYMQHNYJB-UNXOBOICSA-N 0.000 description 2
- OEBXVPQOMXLUJF-UHFFFAOYSA-N [1,2,4]triazolo[1,5-c]quinazolin-5-amine Chemical compound C1=CC=C2C3=NC=NN3C(=N)NC2=C1 OEBXVPQOMXLUJF-UHFFFAOYSA-N 0.000 description 2
- MNFNZCUOKBCMIQ-UHFFFAOYSA-N [1-(oxan-2-yloxy)cyclobutyl]methanol Chemical compound O1C(CCCC1)OC1(CCC1)CO MNFNZCUOKBCMIQ-UHFFFAOYSA-N 0.000 description 2
- RJURFGZVJUQBHK-UHFFFAOYSA-N actinomycin D Natural products CC1OC(=O)C(C(C)C)N(C)C(=O)CN(C)C(=O)C2CCCN2C(=O)C(C(C)C)NC(=O)C1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)NC4C(=O)NC(C(N5CCCC5C(=O)N(C)CC(=O)N(C)C(C(C)C)C(=O)OC4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-UHFFFAOYSA-N 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 238000007792 addition Methods 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 230000000996 additive effect Effects 0.000 description 2
- 239000000443 aerosol Substances 0.000 description 2
- 125000001931 aliphatic group Chemical group 0.000 description 2
- 150000001447 alkali salts Chemical class 0.000 description 2
- 150000001350 alkyl halides Chemical class 0.000 description 2
- 239000002168 alkylating agent Substances 0.000 description 2
- 230000008485 antagonism Effects 0.000 description 2
- 230000000259 anti-tumor effect Effects 0.000 description 2
- 229960005475 antiinfective agent Drugs 0.000 description 2
- 239000004599 antimicrobial Substances 0.000 description 2
- 239000002246 antineoplastic agent Substances 0.000 description 2
- 230000005975 antitumor immune response Effects 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 229910052786 argon Inorganic materials 0.000 description 2
- 208000006673 asthma Diseases 0.000 description 2
- 208000022362 bacterial infectious disease Diseases 0.000 description 2
- 230000003851 biochemical process Effects 0.000 description 2
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000001185 bone marrow Anatomy 0.000 description 2
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 2
- 210000000481 breast Anatomy 0.000 description 2
- 150000001649 bromium compounds Chemical class 0.000 description 2
- 235000013877 carbamide Nutrition 0.000 description 2
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 2
- 238000002512 chemotherapy Methods 0.000 description 2
- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- 230000001684 chronic effect Effects 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 239000013058 crude material Substances 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 229940127089 cytotoxic agent Drugs 0.000 description 2
- 229960000975 daunorubicin Drugs 0.000 description 2
- STQGQHZAVUOBTE-VGBVRHCVSA-N daunorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 description 2
- 210000004443 dendritic cell Anatomy 0.000 description 2
- OYAKEDXODWNSRO-UHFFFAOYSA-N diethyl 2-(3-oxopentyl)propanedioate Chemical compound CCOC(=O)C(C(=O)OCC)CCC(=O)CC OYAKEDXODWNSRO-UHFFFAOYSA-N 0.000 description 2
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 229960004679 doxorubicin Drugs 0.000 description 2
- JPPRZQISIMLKPW-UHFFFAOYSA-N ethyl 3-(4-bromopyrazol-1-yl)propanoate Chemical compound CCOC(=O)CCN1C=C(Br)C=N1 JPPRZQISIMLKPW-UHFFFAOYSA-N 0.000 description 2
- BGAOLPQGOBDXBH-UHFFFAOYSA-N ethyl 3-hydroxycyclohexane-1-carboxylate Chemical compound CCOC(=O)C1CCCC(O)C1 BGAOLPQGOBDXBH-UHFFFAOYSA-N 0.000 description 2
- YLRVJPQVDQQBOX-UHFFFAOYSA-N ethyl 3-oxocyclohexane-1-carboxylate Chemical compound CCOC(=O)C1CCCC(=O)C1 YLRVJPQVDQQBOX-UHFFFAOYSA-N 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- ODKNJVUHOIMIIZ-RRKCRQDMSA-N floxuridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(F)=C1 ODKNJVUHOIMIIZ-RRKCRQDMSA-N 0.000 description 2
- 125000001153 fluoro group Chemical group F* 0.000 description 2
- 239000012634 fragment Substances 0.000 description 2
- 125000003838 furazanyl group Chemical group 0.000 description 2
- 125000002541 furyl group Chemical group 0.000 description 2
- 235000021472 generally recognized as safe Nutrition 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- 150000002367 halogens Chemical class 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 229960000908 idarubicin Drugs 0.000 description 2
- 125000002883 imidazolyl group Chemical group 0.000 description 2
- 230000028993 immune response Effects 0.000 description 2
- 239000002955 immunomodulating agent Substances 0.000 description 2
- 229940121354 immunomodulator Drugs 0.000 description 2
- 230000001506 immunosuppresive effect Effects 0.000 description 2
- 238000009169 immunotherapy Methods 0.000 description 2
- 230000001524 infective effect Effects 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- UEXQBEVWFZKHNB-UHFFFAOYSA-N intermediate 29 Natural products C1=CC(N)=CC=C1NC1=NC=CC=N1 UEXQBEVWFZKHNB-UHFFFAOYSA-N 0.000 description 2
- 150000004694 iodide salts Chemical class 0.000 description 2
- 125000001786 isothiazolyl group Chemical group 0.000 description 2
- 125000000842 isoxazolyl group Chemical group 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- 229910001496 lithium tetrafluoroborate Inorganic materials 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- 201000005202 lung cancer Diseases 0.000 description 2
- 208000020816 lung neoplasm Diseases 0.000 description 2
- 238000007726 management method Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 210000004379 membrane Anatomy 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- OKKJLVBELUTLKV-VMNATFBRSA-N methanol-d1 Chemical compound [2H]OC OKKJLVBELUTLKV-VMNATFBRSA-N 0.000 description 2
- XKTLILHWAIXRMM-UHFFFAOYSA-N methyl 2-(4-bromo-5-methylpyrazol-1-yl)-2-methylpropanoate Chemical compound BrC=1C=NN(C=1C)C(C(=O)OC)(C)C XKTLILHWAIXRMM-UHFFFAOYSA-N 0.000 description 2
- CZMAZUJMOQFCBB-UHFFFAOYSA-N methyl 2-methylidene-5-oxohexanoate Chemical compound COC(=O)C(=C)CCC(C)=O CZMAZUJMOQFCBB-UHFFFAOYSA-N 0.000 description 2
- OGSFGBNZYUWVFP-UHFFFAOYSA-N methyl 4-methylpiperidine-3-carboxylate Chemical compound COC(=O)C1CNCCC1C OGSFGBNZYUWVFP-UHFFFAOYSA-N 0.000 description 2
- 239000002480 mineral oil Substances 0.000 description 2
- 235000010446 mineral oil Nutrition 0.000 description 2
- 210000004877 mucosa Anatomy 0.000 description 2
- 210000000581 natural killer T-cell Anatomy 0.000 description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 125000001715 oxadiazolyl group Chemical group 0.000 description 2
- 125000002971 oxazolyl group Chemical group 0.000 description 2
- 125000003566 oxetanyl group Chemical group 0.000 description 2
- 125000004430 oxygen atom Chemical group O* 0.000 description 2
- MXQOYLRVSVOCQT-UHFFFAOYSA-N palladium;tritert-butylphosphane Chemical compound [Pd].CC(C)(C)P(C(C)(C)C)C(C)(C)C.CC(C)(C)P(C(C)(C)C)C(C)(C)C MXQOYLRVSVOCQT-UHFFFAOYSA-N 0.000 description 2
- 230000037361 pathway Effects 0.000 description 2
- 229940121655 pd-1 inhibitor Drugs 0.000 description 2
- 210000005259 peripheral blood Anatomy 0.000 description 2
- 239000011886 peripheral blood Substances 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- XNQULTQRGBXLIA-UHFFFAOYSA-O phosphonic anhydride Chemical compound O[P+](O)=O XNQULTQRGBXLIA-UHFFFAOYSA-O 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- 238000010837 poor prognosis Methods 0.000 description 2
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- 239000003528 protein farnesyltransferase inhibitor Substances 0.000 description 2
- 125000002098 pyridazinyl group Chemical group 0.000 description 2
- 125000000714 pyrimidinyl group Chemical group 0.000 description 2
- KWHDQPVGKVPPPS-UHFFFAOYSA-N quinazolin-5-amine Chemical compound C1=NC=C2C(N)=CC=CC2=N1 KWHDQPVGKVPPPS-UHFFFAOYSA-N 0.000 description 2
- 230000005855 radiation Effects 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- 230000011664 signaling Effects 0.000 description 2
- 210000003491 skin Anatomy 0.000 description 2
- 208000000587 small cell lung carcinoma Diseases 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 210000000130 stem cell Anatomy 0.000 description 2
- 239000011593 sulfur Substances 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 230000001629 suppression Effects 0.000 description 2
- HFMHEXPZANOFSL-SSDOTTSWSA-N tert-butyl (3r)-3-(hydrazinecarbonyl)pyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CC[C@@H](C(=O)NN)C1 HFMHEXPZANOFSL-SSDOTTSWSA-N 0.000 description 2
- AHRKSRKVAPVECB-UHFFFAOYSA-N tert-butyl 3-(hydrazinecarbonyl)-5-methylpiperidine-1-carboxylate Chemical compound N(N)C(=O)C1CN(CC(C1)C)C(=O)OC(C)(C)C AHRKSRKVAPVECB-UHFFFAOYSA-N 0.000 description 2
- CECIGQRFZHKJDG-UHFFFAOYSA-N tert-butyl N-[1-(4-aminopyrazol-1-yl)-2-methylpropan-2-yl]carbamate Chemical compound CC(C)(C)OC(=O)NC(C)(C)CN1C=C(N)C=N1 CECIGQRFZHKJDG-UHFFFAOYSA-N 0.000 description 2
- 125000001113 thiadiazolyl group Chemical group 0.000 description 2
- 125000000335 thiazolyl group Chemical group 0.000 description 2
- WYWHKKSPHMUBEB-UHFFFAOYSA-N tioguanine Chemical compound N1C(N)=NC(=S)C2=C1N=CN2 WYWHKKSPHMUBEB-UHFFFAOYSA-N 0.000 description 2
- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 description 2
- PYOKUURKVVELLB-UHFFFAOYSA-N trimethyl orthoformate Chemical compound COC(OC)OC PYOKUURKVVELLB-UHFFFAOYSA-N 0.000 description 2
- SIOVKLKJSOKLIF-HJWRWDBZSA-N trimethylsilyl (1z)-n-trimethylsilylethanimidate Chemical compound C[Si](C)(C)OC(/C)=N\[Si](C)(C)C SIOVKLKJSOKLIF-HJWRWDBZSA-N 0.000 description 2
- ONDSBJMLAHVLMI-UHFFFAOYSA-N trimethylsilyldiazomethane Chemical compound C[Si](C)(C)[CH-][N+]#N ONDSBJMLAHVLMI-UHFFFAOYSA-N 0.000 description 2
- JBWKIWSBJXDJDT-UHFFFAOYSA-N triphenylmethyl chloride Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(Cl)C1=CC=CC=C1 JBWKIWSBJXDJDT-UHFFFAOYSA-N 0.000 description 2
- 150000003672 ureas Chemical class 0.000 description 2
- 230000024883 vasodilation Effects 0.000 description 2
- LSPHULWDVZXLIL-UHFFFAOYSA-N (+/-)-Camphoric acid Chemical class CC1(C)C(C(O)=O)CCC1(C)C(O)=O LSPHULWDVZXLIL-UHFFFAOYSA-N 0.000 description 1
- QOWBXWFYRXSBAS-UHFFFAOYSA-N (2,4-dimethoxyphenyl)methanamine Chemical compound COC1=CC=C(CN)C(OC)=C1 QOWBXWFYRXSBAS-UHFFFAOYSA-N 0.000 description 1
- PQXKWPLDPFFDJP-ZXZARUISSA-N (2r,3s)-2,3-dimethyloxirane Chemical compound C[C@H]1O[C@H]1C PQXKWPLDPFFDJP-ZXZARUISSA-N 0.000 description 1
- PAORVUMOXXAMPL-SECBINFHSA-N (2s)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl chloride Chemical compound CO[C@](C(Cl)=O)(C(F)(F)F)C1=CC=CC=C1 PAORVUMOXXAMPL-SECBINFHSA-N 0.000 description 1
- HRMRQBJUFWFQLX-SSDOTTSWSA-N (3r)-1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidine-3-carboxylic acid Chemical compound CC(C)(C)OC(=O)N1CC[C@@H](C(O)=O)C1 HRMRQBJUFWFQLX-SSDOTTSWSA-N 0.000 description 1
- PIUHBEUEYDRWGW-UHFFFAOYSA-N (5-methyl-2-phenyl-1,3-dioxan-5-yl)methanol Chemical compound O1CC(C)(CO)COC1C1=CC=CC=C1 PIUHBEUEYDRWGW-UHFFFAOYSA-N 0.000 description 1
- FPVKHBSQESCIEP-UHFFFAOYSA-N (8S)-3-(2-deoxy-beta-D-erythro-pentofuranosyl)-3,6,7,8-tetrahydroimidazo[4,5-d][1,3]diazepin-8-ol Natural products C1C(O)C(CO)OC1N1C(NC=NCC2O)=C2N=C1 FPVKHBSQESCIEP-UHFFFAOYSA-N 0.000 description 1
- FDKXTQMXEQVLRF-ZHACJKMWSA-N (E)-dacarbazine Chemical compound CN(C)\N=N\c1[nH]cnc1C(N)=O FDKXTQMXEQVLRF-ZHACJKMWSA-N 0.000 description 1
- YPMQYIFFTKAPPZ-UHFFFAOYSA-N 1,1-dioxo-1,4-thiazinane-4-carboxylic acid Chemical compound OC(=O)N1CCS(=O)(=O)CC1 YPMQYIFFTKAPPZ-UHFFFAOYSA-N 0.000 description 1
- 125000005940 1,4-dioxanyl group Chemical group 0.000 description 1
- HKQTYQDNCKMNHZ-UHFFFAOYSA-N 1,4-dioxaspiro[4.5]decan-8-ol Chemical compound C1CC(O)CCC21OCCO2 HKQTYQDNCKMNHZ-UHFFFAOYSA-N 0.000 description 1
- ZIMOOPGHVIFYRK-UHFFFAOYSA-N 1-(3-bromo-1,2,4-triazol-1-yl)-2-methylpropan-2-ol Chemical compound BrC1=NN(C=N1)CC(C)(O)C ZIMOOPGHVIFYRK-UHFFFAOYSA-N 0.000 description 1
- IWFIZPHXPXKRGP-UHFFFAOYSA-N 1-(4-amino-3-methylpyrazol-1-yl)-2-methylpropan-2-ol Chemical compound CC1=NN(CC(C)(C)O)C=C1N IWFIZPHXPXKRGP-UHFFFAOYSA-N 0.000 description 1
- OMJZQGSHLIJGAR-UHFFFAOYSA-N 1-(4-bromopyrazol-1-yl)propan-2-one Chemical compound CC(=O)CN1C=C(Br)C=N1 OMJZQGSHLIJGAR-UHFFFAOYSA-N 0.000 description 1
- AHLQONPFZPGIPL-UHFFFAOYSA-N 1-(4-iodopyrazol-1-yl)-2-methylpropan-2-ol Chemical compound CC(C)(O)CN1C=C(I)C=N1 AHLQONPFZPGIPL-UHFFFAOYSA-N 0.000 description 1
- KTVGYAJQQQUOQX-UHFFFAOYSA-N 1-(hydroxymethyl)cyclobutan-1-ol Chemical compound OCC1(O)CCC1 KTVGYAJQQQUOQX-UHFFFAOYSA-N 0.000 description 1
- XLFCFJGSQOJKFC-UHFFFAOYSA-N 1-[1-(1-hydroxy-2-methylpropan-2-yl)pyrazol-4-yl]-6-methylpiperidine-3-carbohydrazide Chemical compound OCC(C)(C)N1N=CC(=C1)N1CC(CCC1C)C(=O)NN XLFCFJGSQOJKFC-UHFFFAOYSA-N 0.000 description 1
- BFYXSRLBIUSJLT-UHFFFAOYSA-N 1-[1-(2-hydroxy-2-methylpropyl)-5-methylpyrazol-4-yl]-5-methylpiperidine-3-carbohydrazide Chemical compound OC(CN1N=CC(=C1C)N1CC(CC(C1)C)C(=O)NN)(C)C BFYXSRLBIUSJLT-UHFFFAOYSA-N 0.000 description 1
- CBUFEJWSAUUJFS-LSDHHAIUSA-N 1-[4-[(2S,5R)-5-(5-amino-9-fluoro-8-methyl-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl]pyrazol-1-yl]-2-methylpropan-2-ol Chemical compound NC1=NC=2C=C(C(=CC=2C=2N1N=C(N=2)[C@@H]1CC[C@@H](N(C1)C=1C=NN(C=1)CC(C)(O)C)C)F)C CBUFEJWSAUUJFS-LSDHHAIUSA-N 0.000 description 1
- UFUFMCVQSWKUKL-UHFFFAOYSA-N 1-[4-[3-(5-amino-9-fluoro-7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-fluoropiperidin-1-yl]-3-methylpyrazol-1-yl]-2-methylpropan-2-ol Chemical compound COC1=CC(F)=CC2=C1N=C(N)N1N=C(N=C21)C1CC(F)CN(C1)C1=CN(CC(C)(C)O)N=C1C UFUFMCVQSWKUKL-UHFFFAOYSA-N 0.000 description 1
- AVPIEPXTGDCYMJ-UHFFFAOYSA-N 1-[4-[3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-fluoropiperidin-1-yl]pyrazol-1-yl]-2-methylpropan-2-ol Chemical compound COC1=CC2=C(C=C1F)C1=NC(=NN1C(N)=N2)C1CC(F)CN(C1)C1=CN(CC(C)(C)O)N=C1 AVPIEPXTGDCYMJ-UHFFFAOYSA-N 0.000 description 1
- ZGHVEDRQDAFOKF-UHFFFAOYSA-N 1-[4-[5-(5-amino-9-fluoro-7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl]pyrazol-1-yl]-2-methylpropan-2-ol Chemical compound COC1=CC(F)=CC2=C1N=C(N)N1N=C(N=C21)C1CCC(C)N(C1)C1=CN(CC(C)(C)O)N=C1 ZGHVEDRQDAFOKF-UHFFFAOYSA-N 0.000 description 1
- MICMHFIQSAMEJG-UHFFFAOYSA-N 1-bromopyrrolidine-2,5-dione Chemical compound BrN1C(=O)CCC1=O.BrN1C(=O)CCC1=O MICMHFIQSAMEJG-UHFFFAOYSA-N 0.000 description 1
- VFWCMGCRMGJXDK-UHFFFAOYSA-N 1-chlorobutane Chemical class CCCCCl VFWCMGCRMGJXDK-UHFFFAOYSA-N 0.000 description 1
- VUQPJRPDRDVQMN-UHFFFAOYSA-N 1-chlorooctadecane Chemical class CCCCCCCCCCCCCCCCCCCl VUQPJRPDRDVQMN-UHFFFAOYSA-N 0.000 description 1
- CUBAIJGHSDICOZ-UHFFFAOYSA-N 1-o-tert-butyl 3-o-methyl 4-methylpiperidine-1,3-dicarboxylate Chemical compound COC(=O)C1CN(C(=O)OC(C)(C)C)CCC1C CUBAIJGHSDICOZ-UHFFFAOYSA-N 0.000 description 1
- 238000004009 13C{1H}-NMR spectroscopy Methods 0.000 description 1
- GCKMFJBGXUYNAG-UHFFFAOYSA-N 17alpha-methyltestosterone Natural products C1CC2=CC(=O)CCC2(C)C2C1C1CCC(C)(O)C1(C)CC2 GCKMFJBGXUYNAG-UHFFFAOYSA-N 0.000 description 1
- JVVRJMXHNUAPHW-UHFFFAOYSA-N 1h-pyrazol-5-amine Chemical compound NC=1C=CNN=1 JVVRJMXHNUAPHW-UHFFFAOYSA-N 0.000 description 1
- QPBYBLZYMNWGMO-UHFFFAOYSA-N 2,2,3-trimethyloxirane Chemical compound CC1OC1(C)C QPBYBLZYMNWGMO-UHFFFAOYSA-N 0.000 description 1
- LTMRRSWNXVJMBA-UHFFFAOYSA-L 2,2-diethylpropanedioate Chemical compound CCC(CC)(C([O-])=O)C([O-])=O LTMRRSWNXVJMBA-UHFFFAOYSA-L 0.000 description 1
- UWKQJZCTQGMHKD-UHFFFAOYSA-N 2,6-di-tert-butylpyridine Chemical compound CC(C)(C)C1=CC=CC(C(C)(C)C)=N1 UWKQJZCTQGMHKD-UHFFFAOYSA-N 0.000 description 1
- LTRSVZUGCNFAFM-UHFFFAOYSA-N 2-(4-bromo-3-methylpyrazol-1-yl)-2-methylpropan-1-ol Chemical compound BrC=1C(=NN(C=1)C(CO)(C)C)C LTRSVZUGCNFAFM-UHFFFAOYSA-N 0.000 description 1
- WJBLHSPTKUGEEM-UHFFFAOYSA-N 2-(4-bromo-5-methylpyrazol-1-yl)-2-methylpropan-1-ol Chemical compound BrC=1C=NN(C=1C)C(CO)(C)C WJBLHSPTKUGEEM-UHFFFAOYSA-N 0.000 description 1
- ANYZYUZHYHEDJW-UHFFFAOYSA-N 2-(4-bromopyrazol-1-yl)cyclopentan-1-ol Chemical compound OC1CCCC1N1N=CC(Br)=C1 ANYZYUZHYHEDJW-UHFFFAOYSA-N 0.000 description 1
- ADJOYEMKHFQISN-UHFFFAOYSA-N 2-[4-[3-(5-amino-9-fluoro-7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-methylpiperidin-1-yl]pyrazol-1-yl]-2-methylpropan-1-ol Chemical compound COC1=CC(F)=CC2=C1N=C(N)N1N=C(N=C21)C1CC(C)CN(C1)C1=CN(N=C1)C(C)(C)CO ADJOYEMKHFQISN-UHFFFAOYSA-N 0.000 description 1
- WCQCRQDEAFXOES-UHFFFAOYSA-N 2-amino-5-fluoro-3-methoxybenzoic acid Chemical compound COC1=CC(F)=CC(C(O)=O)=C1N WCQCRQDEAFXOES-UHFFFAOYSA-N 0.000 description 1
- ROJASEXNUCZUED-UHFFFAOYSA-N 2-bromo-5,8-dioxaspiro[3.4]octane Chemical compound C1C(Br)CC21OCCO2 ROJASEXNUCZUED-UHFFFAOYSA-N 0.000 description 1
- WSRFQBBRQYLALC-UHFFFAOYSA-N 2-bromo-5-(difluoromethoxy)-4-fluoroaniline Chemical compound Nc1cc(OC(F)F)c(F)cc1Br WSRFQBBRQYLALC-UHFFFAOYSA-N 0.000 description 1
- QNKQNJJCNWUOHC-UHFFFAOYSA-N 2-bromo-5-chloro-4-fluoroaniline Chemical compound NC1=CC(Cl)=C(F)C=C1Br QNKQNJJCNWUOHC-UHFFFAOYSA-N 0.000 description 1
- XQZZIZVMMMRELO-UHFFFAOYSA-N 2-bromocyclobutan-1-one Chemical compound BrC1CCC1=O XQZZIZVMMMRELO-UHFFFAOYSA-N 0.000 description 1
- WRJXKQFRHWSELJ-UHFFFAOYSA-N 2-methyl-1-(3-methyl-4-nitropyrazol-1-yl)propan-2-ol Chemical compound CC(CN1N=C(C(=C1)[N+](=O)[O-])C)(C)O WRJXKQFRHWSELJ-UHFFFAOYSA-N 0.000 description 1
- ATBBKVZAFMJRSG-UHFFFAOYSA-N 2-methyl-1-(5-methyl-4-nitropyrazol-1-yl)propan-2-ol Chemical compound CC(CN1N=CC(=C1C)[N+](=O)[O-])(C)O ATBBKVZAFMJRSG-UHFFFAOYSA-N 0.000 description 1
- NYCBGDUPPBUSPC-UHFFFAOYSA-N 2-oxopiperidine-3-carbohydrazide Chemical compound NNC(=O)C1CCCNC1=O NYCBGDUPPBUSPC-UHFFFAOYSA-N 0.000 description 1
- WMPPDTMATNBGJN-UHFFFAOYSA-N 2-phenylethylbromide Chemical class BrCCC1=CC=CC=C1 WMPPDTMATNBGJN-UHFFFAOYSA-N 0.000 description 1
- AYLLGANDCRGAHU-UHFFFAOYSA-N 3,5-dihydroxy-4,4,6,6-tetramethyl-1-oxido-3a,7-dihydro-2h-imidazo[4,5-c]pyridin-1-ium Chemical compound CC1(C)N(O)C(C)(C)CC2=[N+]([O-])CN(O)C21 AYLLGANDCRGAHU-UHFFFAOYSA-N 0.000 description 1
- RTRPHQRWCXXEKJ-UHFFFAOYSA-N 3-(4-aminopyrazol-1-yl)-2-methylpropane-1,2-diol Chemical compound CC(O)(CO)CN1C=C(N)C=N1 RTRPHQRWCXXEKJ-UHFFFAOYSA-N 0.000 description 1
- UEILAUUPIYYLBD-UHFFFAOYSA-N 3-(4-bromopyrazol-1-yl)-3-methylbutan-2-one Chemical compound BrC=1C=NN(C=1)C(C(C)=O)(C)C UEILAUUPIYYLBD-UHFFFAOYSA-N 0.000 description 1
- FUQHYUVPDLMICC-UHFFFAOYSA-N 3-(4-bromopyrazol-1-yl)propanoic acid Chemical compound OC(=O)CCN1C=C(Br)C=N1 FUQHYUVPDLMICC-UHFFFAOYSA-N 0.000 description 1
- NEFFYNJYMIJRGA-WXRRBKDZSA-N 3-[4-[(3R)-3-(5-amino-7,9-difluoro-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidin-1-yl]pyrazol-1-yl]butan-2-ol Chemical compound CC(O)C(C)N1C=C(C=N1)N1CCC[C@H](C1)C1=NN2C(=N1)C1=C(N=C2N)C(F)=CC(F)=C1 NEFFYNJYMIJRGA-WXRRBKDZSA-N 0.000 description 1
- KRNMNDZPRMXLIZ-UHFFFAOYSA-N 3-amino-2-pentan-2-yl-1h-pyrazol-5-one Chemical compound CCCC(C)N1NC(=O)C=C1N KRNMNDZPRMXLIZ-UHFFFAOYSA-N 0.000 description 1
- ZRPLANDPDWYOMZ-UHFFFAOYSA-N 3-cyclopentylpropionic acid Chemical class OC(=O)CCC1CCCC1 ZRPLANDPDWYOMZ-UHFFFAOYSA-N 0.000 description 1
- VNPUCPQSPVPDPC-UHFFFAOYSA-N 3-fluoro-1-phenylmethoxycarbonylpiperidine-3-carboxylic acid Chemical compound C1C(C(=O)O)(F)CCCN1C(=O)OCC1=CC=CC=C1 VNPUCPQSPVPDPC-UHFFFAOYSA-N 0.000 description 1
- XMIIGOLPHOKFCH-UHFFFAOYSA-N 3-phenylpropionic acid Chemical class OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 description 1
- AOJJSUZBOXZQNB-VTZDEGQISA-N 4'-epidoxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-VTZDEGQISA-N 0.000 description 1
- RTDAMORRDXWYPT-UHFFFAOYSA-N 4,5-dichloro-3,6-dioxocyclohexa-1,4-diene-1,2-dicarbonitrile Chemical compound ClC1=C(Cl)C(=O)C(C#N)=C(C#N)C1=O.ClC1=C(Cl)C(=O)C(C#N)=C(C#N)C1=O RTDAMORRDXWYPT-UHFFFAOYSA-N 0.000 description 1
- FSWYXELJGWZSDY-UHFFFAOYSA-N 4-(3-methoxy-3-oxopropyl)-2,2-dimethyloxane-4-carboxylic acid Chemical compound COC(=O)CCC1(C(O)=O)CCOC(C)(C)C1 FSWYXELJGWZSDY-UHFFFAOYSA-N 0.000 description 1
- IPMSARLBJARXSC-UHFFFAOYSA-N 4-bromo-1-ethylpyrazole Chemical compound CCN1C=C(Br)C=N1 IPMSARLBJARXSC-UHFFFAOYSA-N 0.000 description 1
- IXJSDKIJPVSPKF-UHFFFAOYSA-N 4-bromo-1-methylpyrazole Chemical compound CN1C=C(Br)C=N1 IXJSDKIJPVSPKF-UHFFFAOYSA-N 0.000 description 1
- JGEFVMSUMVPALJ-UHFFFAOYSA-N 4-bromo-3-ethoxy-5-methyl-1h-pyrazole Chemical compound CCOC1=NNC(C)=C1Br JGEFVMSUMVPALJ-UHFFFAOYSA-N 0.000 description 1
- XAACOEWSHBIFGJ-UHFFFAOYSA-N 4-fluoro-3-methoxyaniline Chemical compound COC1=CC(N)=CC=C1F XAACOEWSHBIFGJ-UHFFFAOYSA-N 0.000 description 1
- JTRNQTFTRDPITG-UHFFFAOYSA-N 4-iodooxane Chemical compound IC1CCOCC1 JTRNQTFTRDPITG-UHFFFAOYSA-N 0.000 description 1
- IDPUKCWIGUEADI-UHFFFAOYSA-N 5-[bis(2-chloroethyl)amino]uracil Chemical compound ClCCN(CCCl)C1=CNC(=O)NC1=O IDPUKCWIGUEADI-UHFFFAOYSA-N 0.000 description 1
- NMUSYJAQQFHJEW-KVTDHHQDSA-N 5-azacytidine Chemical compound O=C1N=C(N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 NMUSYJAQQFHJEW-KVTDHHQDSA-N 0.000 description 1
- DJDHHXDFKSLEQY-UHFFFAOYSA-N 5-methylpyridine-3-carboxylic acid Chemical compound CC1=CN=CC(C(O)=O)=C1 DJDHHXDFKSLEQY-UHFFFAOYSA-N 0.000 description 1
- MZRUFMBFIKGOAL-UHFFFAOYSA-N 5-nitro-1h-pyrazole Chemical compound [O-][N+](=O)C1=CC=NN1 MZRUFMBFIKGOAL-UHFFFAOYSA-N 0.000 description 1
- HRUYBRGMRSNLNW-UHFFFAOYSA-N 6-methoxy-2-[(4-methylphenyl)methylsulfanyl]-1h-benzimidazole Chemical compound N1C2=CC(OC)=CC=C2N=C1SCC1=CC=C(C)C=C1 HRUYBRGMRSNLNW-UHFFFAOYSA-N 0.000 description 1
- JQGMJVAGMKWLPX-UHFFFAOYSA-N 9-chloro-7-methoxy-2-[1-(1-methylpyrazol-4-yl)piperidin-3-yl]-[1,2,4]triazolo[1,5-c]quinazolin-5-amine Chemical compound COC1=C2N=C(N)N3N=C(N=C3C2=CC(Cl)=C1)C1CCCN(C1)C1=CN(C)N=C1 JQGMJVAGMKWLPX-UHFFFAOYSA-N 0.000 description 1
- ZKHQWZAMYRWXGA-KQYNXXCUSA-J ATP(4-) Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP([O-])(=O)OP([O-])(=O)OP([O-])([O-])=O)[C@@H](O)[C@H]1O ZKHQWZAMYRWXGA-KQYNXXCUSA-J 0.000 description 1
- 229930024421 Adenine Natural products 0.000 description 1
- GFFGJBXGBJISGV-UHFFFAOYSA-N Adenine Chemical compound NC1=NC=NC2=C1N=CN2 GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 108091008875 B cell receptors Proteins 0.000 description 1
- 108010006654 Bleomycin Proteins 0.000 description 1
- NWDQPXKSFTTZGT-UHFFFAOYSA-N BrC=1C(=NN(C=1)C(C1=CC=CC=C1)(C1=CC=CC=C1)C1=CC=CC=C1)C(F)F Chemical compound BrC=1C(=NN(C=1)C(C1=CC=CC=C1)(C1=CC=CC=C1)C1=CC=CC=C1)C(F)F NWDQPXKSFTTZGT-UHFFFAOYSA-N 0.000 description 1
- UZGGUMITVDNZRJ-YPBKCWQDSA-N BrC=1C=NN(C=1)[C@@H](C)[C@@H](C)OC1OCCCC1 Chemical compound BrC=1C=NN(C=1)[C@@H](C)[C@@H](C)OC1OCCCC1 UZGGUMITVDNZRJ-YPBKCWQDSA-N 0.000 description 1
- QFBRHKIAELUQKF-UHFFFAOYSA-N BrC=1C=NN(C=1C(F)F)C(C1=CC=CC=C1)(C1=CC=CC=C1)C1=CC=CC=C1 Chemical compound BrC=1C=NN(C=1C(F)F)C(C1=CC=CC=C1)(C1=CC=CC=C1)C1=CC=CC=C1 QFBRHKIAELUQKF-UHFFFAOYSA-N 0.000 description 1
- JUNVQNWMGITFIZ-CYBMUJFWSA-N C(C)(C)(C)N1N=CC(=C1)N1C[C@@H](CCC1)C1=NN2C(=NC=3C=C(C(=CC=3C2=N1)F)OC)N Chemical compound C(C)(C)(C)N1N=CC(=C1)N1C[C@@H](CCC1)C1=NN2C(=NC=3C=C(C(=CC=3C2=N1)F)OC)N JUNVQNWMGITFIZ-CYBMUJFWSA-N 0.000 description 1
- DVMHQMMLFPDDLU-UHFFFAOYSA-N C(C)(C)(C)OC(=O)N1CC(CCC1)C1=NN2C(=NC=3C=C(C(=CC=3C2=N1)F)OC(F)F)O Chemical compound C(C)(C)(C)OC(=O)N1CC(CCC1)C1=NN2C(=NC=3C=C(C(=CC=3C2=N1)F)OC(F)F)O DVMHQMMLFPDDLU-UHFFFAOYSA-N 0.000 description 1
- 101710112622 C-C motif chemokine 19 Proteins 0.000 description 1
- 102100021943 C-C motif chemokine 2 Human genes 0.000 description 1
- 101710155857 C-C motif chemokine 2 Proteins 0.000 description 1
- NKFAJVJWMKAUIQ-UHFFFAOYSA-N C1(C)N(CC(CC1)C(=O)NN)C1=CN(N=C1)C(CO)(C)CO Chemical compound C1(C)N(CC(CC1)C(=O)NN)C1=CN(N=C1)C(CO)(C)CO NKFAJVJWMKAUIQ-UHFFFAOYSA-N 0.000 description 1
- MSCBXYVWRMPYJS-UHFFFAOYSA-N C1(CCC(C)N(C1)C1=CN(N=C1)C1CCC2(OCCO2)CC1)C(=O)OCC Chemical compound C1(CCC(C)N(C1)C1=CN(N=C1)C1CCC2(OCCO2)CC1)C(=O)OCC MSCBXYVWRMPYJS-UHFFFAOYSA-N 0.000 description 1
- LJMBGFFRMXAHKS-UHFFFAOYSA-N C1=C(C(=CC2=C1C1=NC(C3CN(CC(C3)C)C=3C(C)=NN(C=3)CC(C)(C)O)=NN1C(=N2)N)OC)F Chemical compound C1=C(C(=CC2=C1C1=NC(C3CN(CC(C3)C)C=3C(C)=NN(C=3)CC(C)(C)O)=NN1C(=N2)N)OC)F LJMBGFFRMXAHKS-UHFFFAOYSA-N 0.000 description 1
- BQPXQEUHRHDFBV-GOSISDBHSA-N C1=C(C(OC)=CC2=C1C1=NC([C@@H]3OCCN(C3)C3=CN(CC(O)(C)C)N=C3C)=NN1C(=N2)N)F Chemical compound C1=C(C(OC)=CC2=C1C1=NC([C@@H]3OCCN(C3)C3=CN(CC(O)(C)C)N=C3C)=NN1C(=N2)N)F BQPXQEUHRHDFBV-GOSISDBHSA-N 0.000 description 1
- LTKHPMDRMUCUEB-IBGZPJMESA-N CB3717 Chemical compound C=1C=C2NC(N)=NC(=O)C2=CC=1CN(CC#C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 LTKHPMDRMUCUEB-IBGZPJMESA-N 0.000 description 1
- XJVPUCRKPKZQTH-UHFFFAOYSA-N CC(C(C)=O)(C)N1N=CC(=C1)[N+](=O)[O-] Chemical compound CC(C(C)=O)(C)N1N=CC(=C1)[N+](=O)[O-] XJVPUCRKPKZQTH-UHFFFAOYSA-N 0.000 description 1
- USGCFCCLWDBEMW-UHFFFAOYSA-N CC(C)(C)OC(=O)N1CCC(F)(C1)C(=O)NN Chemical compound CC(C)(C)OC(=O)N1CCC(F)(C1)C(=O)NN USGCFCCLWDBEMW-UHFFFAOYSA-N 0.000 description 1
- UVDLKCZDFDAKBM-UHFFFAOYSA-N CC(CN1N=CC(=C1)[N+](=O)[O-])(C)NC(OC(C)(C)C)=O Chemical compound CC(CN1N=CC(=C1)[N+](=O)[O-])(C)NC(OC(C)(C)C)=O UVDLKCZDFDAKBM-UHFFFAOYSA-N 0.000 description 1
- YHORRJDHQMTHOT-UHFFFAOYSA-N CC(CO)(CN1N=CC(=C1)[N+](=O)[O-])O Chemical compound CC(CO)(CN1N=CC(=C1)[N+](=O)[O-])O YHORRJDHQMTHOT-UHFFFAOYSA-N 0.000 description 1
- XFIDNJIHTUNTBV-JXQTWKCFSA-N CC(O)C(C)N1C=C(N2CCC[C@H](C2)C2=NN3C(=N2)C2=C(N=C3N)C(F)=CC(F)=C2)C(C)=N1 Chemical compound CC(O)C(C)N1C=C(N2CCC[C@H](C2)C2=NN3C(=N2)C2=C(N=C3N)C(F)=CC(F)=C2)C(C)=N1 XFIDNJIHTUNTBV-JXQTWKCFSA-N 0.000 description 1
- BUTFUAWPAPPDSP-UHFFFAOYSA-N CC1(CN2C=C(N)C=N2)COC(OC1)C1=CC=CC=C1 Chemical compound CC1(CN2C=C(N)C=N2)COC(OC1)C1=CC=CC=C1 BUTFUAWPAPPDSP-UHFFFAOYSA-N 0.000 description 1
- JQFKDUOWHYFKOK-UHFFFAOYSA-N CC1CC(CN(C1)C1=CN(CC(C)(C)O)N=C1)C1=NN2C(=N1)C1=C(N=C2N)C(F)=CC(F)=C1 Chemical compound CC1CC(CN(C1)C1=CN(CC(C)(C)O)N=C1)C1=NN2C(=N1)C1=C(N=C2N)C(F)=CC(F)=C1 JQFKDUOWHYFKOK-UHFFFAOYSA-N 0.000 description 1
- FBXXMLFCQCJNKT-UHFFFAOYSA-N CC1CC(CN(C1)C1=CN(N=C1C)C(C)(C)CO)C1=NN2C(=N1)C1=C(N=C2N)C(F)=CC(F)=C1 Chemical compound CC1CC(CN(C1)C1=CN(N=C1C)C(C)(C)CO)C1=NN2C(=N1)C1=C(N=C2N)C(F)=CC(F)=C1 FBXXMLFCQCJNKT-UHFFFAOYSA-N 0.000 description 1
- TXIZDQAPSSNEMT-UHFFFAOYSA-N CC1CCC(CN1C2=CN(N=C2)C3CCC4(CC3)OCCO4)C(=O)O Chemical compound CC1CCC(CN1C2=CN(N=C2)C3CCC4(CC3)OCCO4)C(=O)O TXIZDQAPSSNEMT-UHFFFAOYSA-N 0.000 description 1
- LQRNWAHSGGUELB-UHFFFAOYSA-N CC1CCN(CC1C(=O)NN)C(=O)OC(C)(C)C Chemical compound CC1CCN(CC1C(=O)NN)C(=O)OC(C)(C)C LQRNWAHSGGUELB-UHFFFAOYSA-N 0.000 description 1
- IMMKBHZFVZBCEO-PDNQZYNLSA-N CCC(C)(O)CN1C=C(C=N1)N1CCC[C@H](C1)C1=NN2C(=N1)C1=C(C=C(OC)C(F)=C1)N=C2N Chemical compound CCC(C)(O)CN1C=C(C=N1)N1CCC[C@H](C1)C1=NN2C(=N1)C1=C(C=C(OC)C(F)=C1)N=C2N IMMKBHZFVZBCEO-PDNQZYNLSA-N 0.000 description 1
- JGLMVXWAHNTPRF-CMDGGOBGSA-N CCN1N=C(C)C=C1C(=O)NC1=NC2=CC(=CC(OC)=C2N1C\C=C\CN1C(NC(=O)C2=CC(C)=NN2CC)=NC2=CC(=CC(OCCCN3CCOCC3)=C12)C(N)=O)C(N)=O Chemical compound CCN1N=C(C)C=C1C(=O)NC1=NC2=CC(=CC(OC)=C2N1C\C=C\CN1C(NC(=O)C2=CC(C)=NN2CC)=NC2=CC(=CC(OCCCN3CCOCC3)=C12)C(N)=O)C(N)=O JGLMVXWAHNTPRF-CMDGGOBGSA-N 0.000 description 1
- PFVRPDRALZZXQJ-UHFFFAOYSA-N CCOC(=O)C(=C)CCC(C)=O Chemical compound CCOC(=O)C(=C)CCC(C)=O PFVRPDRALZZXQJ-UHFFFAOYSA-N 0.000 description 1
- 108010029697 CD40 Ligand Proteins 0.000 description 1
- 102100032937 CD40 ligand Human genes 0.000 description 1
- ALWIFSZUTHMQCL-UHFFFAOYSA-N CN1C=C(C=N1)N1CCCC(C1)C1=NN2C(=N1)C1=C(F)C(F)=CC=C1N=C2N Chemical compound CN1C=C(C=N1)N1CCCC(C1)C1=NN2C(=N1)C1=C(F)C(F)=CC=C1N=C2N ALWIFSZUTHMQCL-UHFFFAOYSA-N 0.000 description 1
- AVOBSDIPGJUDLP-UHFFFAOYSA-N CN1C=C(C=N1)N1CCCC(C1)C1=NN2C(=N1)C1=CC(Cl)=CC(C)=C1N=C2N Chemical compound CN1C=C(C=N1)N1CCCC(C1)C1=NN2C(=N1)C1=CC(Cl)=CC(C)=C1N=C2N AVOBSDIPGJUDLP-UHFFFAOYSA-N 0.000 description 1
- WCMLJDYBACNZPV-UHFFFAOYSA-N CN1C=C(C=N1)N1CCCC(C1)C1=NN2C(=N1)C1=CC(Cl)=CC=C1N=C2N Chemical compound CN1C=C(C=N1)N1CCCC(C1)C1=NN2C(=N1)C1=CC(Cl)=CC=C1N=C2N WCMLJDYBACNZPV-UHFFFAOYSA-N 0.000 description 1
- SGHYPEPQNIVIBW-UHFFFAOYSA-N CN1C=C(C=N1)N1CCCC(C1)C1=NN2C(=N1)C1=CC(F)=C(F)C=C1N=C2N Chemical compound CN1C=C(C=N1)N1CCCC(C1)C1=NN2C(=N1)C1=CC(F)=C(F)C=C1N=C2N SGHYPEPQNIVIBW-UHFFFAOYSA-N 0.000 description 1
- VINJVTSUJSHSLG-UHFFFAOYSA-N CN1C=C(C=N1)N1CCCC(C1)C1=NN2C(=N1)C1=CC(F)=CC(F)=C1N=C2N Chemical compound CN1C=C(C=N1)N1CCCC(C1)C1=NN2C(=N1)C1=CC(F)=CC(F)=C1N=C2N VINJVTSUJSHSLG-UHFFFAOYSA-N 0.000 description 1
- IVOLXGNWTIEKTP-UHFFFAOYSA-N CN1C=C(C=N1)N1CCCC(C1)C1=NN2C(=N1)C1=CC(F)=CC=C1N=C2N Chemical compound CN1C=C(C=N1)N1CCCC(C1)C1=NN2C(=N1)C1=CC(F)=CC=C1N=C2N IVOLXGNWTIEKTP-UHFFFAOYSA-N 0.000 description 1
- PJHPYOFIJLJSAA-UHFFFAOYSA-N COC1=C(CN=C=NC2=C(C#N)C=C(C(=C2)C)F)C=CC(=C1)OC Chemical compound COC1=C(CN=C=NC2=C(C#N)C=C(C(=C2)C)F)C=CC(=C1)OC PJHPYOFIJLJSAA-UHFFFAOYSA-N 0.000 description 1
- HEMUJTZFWHWCQE-UHFFFAOYSA-N COC1=C(CNC2=NC=3C=C(C(=CC=3C=3N2N=C(N=3)C2C(NCCC2)=O)F)OC)C=CC(=C1)OC Chemical compound COC1=C(CNC2=NC=3C=C(C(=CC=3C=3N2N=C(N=3)C2C(NCCC2)=O)F)OC)C=CC(=C1)OC HEMUJTZFWHWCQE-UHFFFAOYSA-N 0.000 description 1
- FBONFPATKKLDMI-HOCLYGCPSA-N COC1=C(CNC2=NC=3C=C(C(=CC=3C=3N2N=C(N=3)[C@@H]2CNC[C@H](C2)C)F)OC)C=CC(=C1)OC Chemical compound COC1=C(CNC2=NC=3C=C(C(=CC=3C=3N2N=C(N=3)[C@@H]2CNC[C@H](C2)C)F)OC)C=CC(=C1)OC FBONFPATKKLDMI-HOCLYGCPSA-N 0.000 description 1
- LIAGTDIYOXLLEO-HXUWFJFHSA-N COC1=C(CNC2=NC=3C=C(C(=CC=3C=3N2N=C(N=3)[C@H]2CNCCO2)F)OC)C=CC(=C1)OC Chemical compound COC1=C(CNC2=NC=3C=C(C(=CC=3C=3N2N=C(N=3)[C@H]2CNCCO2)F)OC)C=CC(=C1)OC LIAGTDIYOXLLEO-HXUWFJFHSA-N 0.000 description 1
- FBONFPATKKLDMI-GOEBONIOSA-N COC1=C(CNC2=NC=3C=C(C(=CC=3C=3N2N=C(N=3)[C@H]2CNC[C@H](C2)C)F)OC)C=CC(=C1)OC Chemical compound COC1=C(CNC2=NC=3C=C(C(=CC=3C=3N2N=C(N=3)[C@H]2CNC[C@H](C2)C)F)OC)C=CC(=C1)OC FBONFPATKKLDMI-GOEBONIOSA-N 0.000 description 1
- YTNZYBALJMAYQB-UHFFFAOYSA-N COC1=C(F)C=C2C3=NC(=NN3C(N)=NC2=C1)C12CC1CN(C2)C1=CN(CC(C)(C)O)N=C1 Chemical compound COC1=C(F)C=C2C3=NC(=NN3C(N)=NC2=C1)C12CC1CN(C2)C1=CN(CC(C)(C)O)N=C1 YTNZYBALJMAYQB-UHFFFAOYSA-N 0.000 description 1
- JRPAGDUZNIVMGV-UHFFFAOYSA-N COC1=CC(F)=CC2=C1N=C(N)N1N=C(N=C21)C1CC(C)CN(C1)C1=C(C)N(CC(C)(C)O)N=C1 Chemical compound COC1=CC(F)=CC2=C1N=C(N)N1N=C(N=C21)C1CC(C)CN(C1)C1=C(C)N(CC(C)(C)O)N=C1 JRPAGDUZNIVMGV-UHFFFAOYSA-N 0.000 description 1
- LFWFKHQPUWTRMT-UHFFFAOYSA-N COC1=CC(F)=CC2=C1N=C(N)N1N=C(N=C21)C1CC(C)CN(C1)C1=CN(N=C1C)C(C)(C)CO Chemical compound COC1=CC(F)=CC2=C1N=C(N)N1N=C(N=C21)C1CC(C)CN(C1)C1=CN(N=C1C)C(C)(C)CO LFWFKHQPUWTRMT-UHFFFAOYSA-N 0.000 description 1
- SZGZDXZMEIQBRL-UHFFFAOYSA-N COC1=CC(F)=CC2=C1N=C(N)N1N=C(N=C21)C1CCC(C)N(C1)C1=CN(N=C1)C(C)(C)CO Chemical compound COC1=CC(F)=CC2=C1N=C(N)N1N=C(N=C21)C1CCC(C)N(C1)C1=CN(N=C1)C(C)(C)CO SZGZDXZMEIQBRL-UHFFFAOYSA-N 0.000 description 1
- RYUJYXYPYRXPTK-PESDSKBTSA-N COC1=CC(F)=CC2=C1N=C(N)N1N=C(N=C21)[C@@H]1CCCN(C1)C1=C(C)N(N=C1)C(C)C(C)O Chemical compound COC1=CC(F)=CC2=C1N=C(N)N1N=C(N=C21)[C@@H]1CCCN(C1)C1=C(C)N(N=C1)C(C)C(C)O RYUJYXYPYRXPTK-PESDSKBTSA-N 0.000 description 1
- KXQJKYKALIPNNM-JXQTWKCFSA-N COC1=CC(F)=CC2=C1N=C(N)N1N=C(N=C21)[C@@H]1CCCN(C1)C1=CN(N=C1)C(C)C(C)O Chemical compound COC1=CC(F)=CC2=C1N=C(N)N1N=C(N=C21)[C@@H]1CCCN(C1)C1=CN(N=C1)C(C)C(C)O KXQJKYKALIPNNM-JXQTWKCFSA-N 0.000 description 1
- QPCXKEGURWUDNH-YMAMQOFZSA-N COC1=CC(F)=CC2=C1N=C(N)N1N=C(N=C21)[C@@H]1CCCN(C1)C1=CN(N=C1C)C(C)C(C)O Chemical compound COC1=CC(F)=CC2=C1N=C(N)N1N=C(N=C21)[C@@H]1CCCN(C1)C1=CN(N=C1C)C(C)C(C)O QPCXKEGURWUDNH-YMAMQOFZSA-N 0.000 description 1
- DJECVAZKAZCXSG-UHFFFAOYSA-N COC1=CC2=C(C=C1F)C1=NC(=NN1C(N)=N2)C1(F)CCN(C1)C1=CN(CC(C)(C)O)N=C1 Chemical compound COC1=CC2=C(C=C1F)C1=NC(=NN1C(N)=N2)C1(F)CCN(C1)C1=CN(CC(C)(C)O)N=C1 DJECVAZKAZCXSG-UHFFFAOYSA-N 0.000 description 1
- DCLLKPBALLQGLK-UHFFFAOYSA-N COC1=CC2=C(C=C1F)C1=NC(=NN1C(N)=N2)C1CC(C)CN(C1)C1=CN(N=C1)C(C)(C)CO Chemical compound COC1=CC2=C(C=C1F)C1=NC(=NN1C(N)=N2)C1CC(C)CN(C1)C1=CN(N=C1)C(C)(C)CO DCLLKPBALLQGLK-UHFFFAOYSA-N 0.000 description 1
- AAUQTTUTLFILEE-UHFFFAOYSA-N COC1=CC2=C(C=C1F)C1=NC(=NN1C(N)=N2)C1CC(F)CN(C1)C1=CN(N=C1)C1CCOCC1 Chemical compound COC1=CC2=C(C=C1F)C1=NC(=NN1C(N)=N2)C1CC(F)CN(C1)C1=CN(N=C1)C1CCOCC1 AAUQTTUTLFILEE-UHFFFAOYSA-N 0.000 description 1
- OWRRPOLRLXUGFQ-UHFFFAOYSA-N COC1=CC2=C(C=C1F)C1=NC(=NN1C(N)=N2)C1CCC(C)N(C1)C1=C(C)N(CC(C)(C)O)N=C1 Chemical compound COC1=CC2=C(C=C1F)C1=NC(=NN1C(N)=N2)C1CCC(C)N(C1)C1=C(C)N(CC(C)(C)O)N=C1 OWRRPOLRLXUGFQ-UHFFFAOYSA-N 0.000 description 1
- WUNVGZMQDISFMR-UHFFFAOYSA-N COC1=CC2=C(C=C1F)C1=NC(=NN1C(N)=N2)C1CCC(C)N(C1)C1=C(C)N(N=C1)C1CCOCC1 Chemical compound COC1=CC2=C(C=C1F)C1=NC(=NN1C(N)=N2)C1CCC(C)N(C1)C1=C(C)N(N=C1)C1CCOCC1 WUNVGZMQDISFMR-UHFFFAOYSA-N 0.000 description 1
- HUVODKWZOQWRCI-UHFFFAOYSA-N COC1=CC2=C(C=C1F)C1=NC(=NN1C(N)=N2)C1CCC(C)N(C1)C1=CN(CC(C)(C)O)N=C1C Chemical compound COC1=CC2=C(C=C1F)C1=NC(=NN1C(N)=N2)C1CCC(C)N(C1)C1=CN(CC(C)(C)O)N=C1C HUVODKWZOQWRCI-UHFFFAOYSA-N 0.000 description 1
- RTTLGBAFQIOJQU-UHFFFAOYSA-N COC1=CC2=C(C=C1F)C1=NC(=NN1C(N)=N2)C1CCC(C)N(C1)C1=CN(N=C1)C(C)(C)C(C)(C)O Chemical compound COC1=CC2=C(C=C1F)C1=NC(=NN1C(N)=N2)C1CCC(C)N(C1)C1=CN(N=C1)C(C)(C)C(C)(C)O RTTLGBAFQIOJQU-UHFFFAOYSA-N 0.000 description 1
- DTAGSSSSNKERPO-UHFFFAOYSA-N COC1=CC2=C(C=C1F)C1=NC(=NN1C(N)=N2)C1CCC(C)N(C1)C1=CN(N=C1)C(C)(C)CO Chemical compound COC1=CC2=C(C=C1F)C1=NC(=NN1C(N)=N2)C1CCC(C)N(C1)C1=CN(N=C1)C(C)(C)CO DTAGSSSSNKERPO-UHFFFAOYSA-N 0.000 description 1
- XABFJTJSLRYOEG-UHFFFAOYSA-N COC1=CC2=C(C=C1F)C1=NC(=NN1C(N)=N2)C1CN(CCC1C)C1=CN(CC(C)(C)O)N=C1 Chemical compound COC1=CC2=C(C=C1F)C1=NC(=NN1C(N)=N2)C1CN(CCC1C)C1=CN(CC(C)(C)O)N=C1 XABFJTJSLRYOEG-UHFFFAOYSA-N 0.000 description 1
- RMXJPHGZSPFTND-PESDSKBTSA-N COC1=CC2=C(C=C1F)C1=NC(=NN1C(N)=N2)[C@@H]1CCCN(C1)C1=C(C)N(N=C1)C(C)C(C)O Chemical compound COC1=CC2=C(C=C1F)C1=NC(=NN1C(N)=N2)[C@@H]1CCCN(C1)C1=C(C)N(N=C1)C(C)C(C)O RMXJPHGZSPFTND-PESDSKBTSA-N 0.000 description 1
- KDRQPCARSPSUSC-ARLHGKGLSA-N COC1=CC2=C(C=C1F)C1=NC(=NN1C(N)=N2)[C@@H]1CCCN(C1)C1=CN(N=C1)C(C)C(C)(C)O Chemical compound COC1=CC2=C(C=C1F)C1=NC(=NN1C(N)=N2)[C@@H]1CCCN(C1)C1=CN(N=C1)C(C)C(C)(C)O KDRQPCARSPSUSC-ARLHGKGLSA-N 0.000 description 1
- CYAPZEQOLHIBHC-JXQTWKCFSA-N COC1=CC2=C(C=C1F)C1=NC(=NN1C(N)=N2)[C@@H]1CCCN(C1)C1=CN(N=C1)C(C)C(C)O Chemical compound COC1=CC2=C(C=C1F)C1=NC(=NN1C(N)=N2)[C@@H]1CCCN(C1)C1=CN(N=C1)C(C)C(C)O CYAPZEQOLHIBHC-JXQTWKCFSA-N 0.000 description 1
- AVPIEPXTGDCYMJ-CHWSQXEVSA-N COC1=CC2=C(C=C1F)C1=NC(=NN1C(N)=N2)[C@@H]1C[C@@H](F)CN(C1)C1=CN(CC(C)(C)O)N=C1 Chemical compound COC1=CC2=C(C=C1F)C1=NC(=NN1C(N)=N2)[C@@H]1C[C@@H](F)CN(C1)C1=CN(CC(C)(C)O)N=C1 AVPIEPXTGDCYMJ-CHWSQXEVSA-N 0.000 description 1
- GORCBFZMQPKZMQ-UHFFFAOYSA-N COC1=CC=C2N=C(N)N3N=C(N=C3C2=C1)C1CCCN(C1)C1=CN(C)N=C1 Chemical compound COC1=CC=C2N=C(N)N3N=C(N=C3C2=C1)C1CCCN(C1)C1=CN(C)N=C1 GORCBFZMQPKZMQ-UHFFFAOYSA-N 0.000 description 1
- LMZIUYJWUNJBIP-UHFFFAOYSA-N COC1=CC=CC(CN=C=NC(C(OC)=CC(F)=C2)=C2C#N)=C1OC Chemical compound COC1=CC=CC(CN=C=NC(C(OC)=CC(F)=C2)=C2C#N)=C1OC LMZIUYJWUNJBIP-UHFFFAOYSA-N 0.000 description 1
- DHBQRBWDRNISFZ-UHFFFAOYSA-N COC1=NN2C(=NC=3C=CC=CC3C2=N1)N Chemical compound COC1=NN2C(=NC=3C=CC=CC3C2=N1)N DHBQRBWDRNISFZ-UHFFFAOYSA-N 0.000 description 1
- OKKCDDNPERKWBO-TZCPDBFXSA-N C[C@@H]1CC[C@@H](CN1C2=CN(N=C2)C3CCC(CC3)(C)O)C4=NN5C(=N4)C6=CC(=C(C=C6N=C5N)OC)F Chemical compound C[C@@H]1CC[C@@H](CN1C2=CN(N=C2)C3CCC(CC3)(C)O)C4=NN5C(=N4)C6=CC(=C(C=C6N=C5N)OC)F OKKCDDNPERKWBO-TZCPDBFXSA-N 0.000 description 1
- 101100054570 Caenorhabditis elegans acn-1 gene Proteins 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-NJFSPNSNSA-N Carbon-14 Chemical compound [14C] OKTJSMMVPCPJKN-NJFSPNSNSA-N 0.000 description 1
- DLGOEMSEDOSKAD-UHFFFAOYSA-N Carmustine Chemical compound ClCCNC(=O)N(N=O)CCCl DLGOEMSEDOSKAD-UHFFFAOYSA-N 0.000 description 1
- JWBOIMRXGHLCPP-UHFFFAOYSA-N Chloditan Chemical compound C=1C=CC=C(Cl)C=1C(C(Cl)Cl)C1=CC=C(Cl)C=C1 JWBOIMRXGHLCPP-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 208000006332 Choriocarcinoma Diseases 0.000 description 1
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 1
- DRPFIPAHCCVCCQ-UHFFFAOYSA-N ClC=1C(=C(C#N)C=C(C=1)Cl)N=C=NCC1=C(C=C(C=C1)OC)OC Chemical compound ClC=1C(=C(C#N)C=C(C=1)Cl)N=C=NCC1=C(C=C(C=C1)OC)OC DRPFIPAHCCVCCQ-UHFFFAOYSA-N 0.000 description 1
- UDMBCSSLTHHNCD-UHFFFAOYSA-N Coenzym Q(11) Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(O)=O)C(O)C1O UDMBCSSLTHHNCD-UHFFFAOYSA-N 0.000 description 1
- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 1
- 241000709687 Coxsackievirus Species 0.000 description 1
- IVOMOUWHDPKRLL-KQYNXXCUSA-N Cyclic adenosine monophosphate Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=CN=C2N)=C2N=C1 IVOMOUWHDPKRLL-KQYNXXCUSA-N 0.000 description 1
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 1
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- 229940124087 DNA topoisomerase II inhibitor Drugs 0.000 description 1
- 108010092160 Dactinomycin Proteins 0.000 description 1
- 208000020401 Depressive disease Diseases 0.000 description 1
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical class C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 1
- 101710121366 Disintegrin and metalloproteinase domain-containing protein 11 Proteins 0.000 description 1
- 208000012661 Dyskinesia Diseases 0.000 description 1
- HTIJFSOGRVMCQR-UHFFFAOYSA-N Epirubicin Natural products COc1cccc2C(=O)c3c(O)c4CC(O)(CC(OC5CC(N)C(=O)C(C)O5)c4c(O)c3C(=O)c12)C(=O)CO HTIJFSOGRVMCQR-UHFFFAOYSA-N 0.000 description 1
- BFPYWIDHMRZLRN-SLHNCBLASA-N Ethinyl estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=C1 BFPYWIDHMRZLRN-SLHNCBLASA-N 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- 208000027776 Extrapyramidal disease Diseases 0.000 description 1
- HVNSRYLUWCANPB-UHFFFAOYSA-N FC(C(=O)O)(F)F.BrC=1C=NN(C1)C1C(CCC1)(O)C Chemical compound FC(C(=O)O)(F)F.BrC=1C=NN(C1)C1C(CCC1)(O)C HVNSRYLUWCANPB-UHFFFAOYSA-N 0.000 description 1
- XSNCWCSRSYYUOC-CYBMUJFWSA-N FC(C1=NN(C=C1N1C[C@@H](CCC1)C1=NN2C(=NC=3C=C(C(=CC=3C2=N1)F)OC)N)C1CCOCC1)F Chemical compound FC(C1=NN(C=C1N1C[C@@H](CCC1)C1=NN2C(=NC=3C=C(C(=CC=3C2=N1)F)OC)N)C1CCOCC1)F XSNCWCSRSYYUOC-CYBMUJFWSA-N 0.000 description 1
- JNPGRTPTDIZDJT-GFCCVEGCSA-N FC(OC1=C(C=C(C=N1)N1C[C@@H](CCC1)C1=NN2C(=NC=3C=C(C(=CC=3C2=N1)F)OC)N)C)F Chemical compound FC(OC1=C(C=C(C=N1)N1C[C@@H](CCC1)C1=NN2C(=NC=3C=C(C(=CC=3C2=N1)F)OC)N)C)F JNPGRTPTDIZDJT-GFCCVEGCSA-N 0.000 description 1
- SDWILZMGHHLTRW-LLVKDONJSA-N FC(OC1=CC=C(C=N1)N1C[C@@H](CCC1)C1=NN2C(=NC=3C(=CC(=CC=3C2=N1)F)OC)N)F Chemical compound FC(OC1=CC=C(C=N1)N1C[C@@H](CCC1)C1=NN2C(=NC=3C(=CC(=CC=3C2=N1)F)OC)N)F SDWILZMGHHLTRW-LLVKDONJSA-N 0.000 description 1
- QTCOGUKLLNNFSH-LLVKDONJSA-N FC(OC1=CC=C(C=N1)N1C[C@@H](CCC1)C1=NN2C(=NC=3C=C(C(=CC=3C2=N1)F)OC)N)F Chemical compound FC(OC1=CC=C(C=N1)N1C[C@@H](CCC1)C1=NN2C(=NC=3C=C(C(=CC=3C2=N1)F)OC)N)F QTCOGUKLLNNFSH-LLVKDONJSA-N 0.000 description 1
- XKOYYBQSPAYHQL-GFCCVEGCSA-N FC1=CC=2C=3N(C(=NC=2C(=C1)OC)N)N=C(N=3)[C@H]1CN(CCC1)C=1C=NC(=CC=1)OC Chemical compound FC1=CC=2C=3N(C(=NC=2C(=C1)OC)N)N=C(N=3)[C@H]1CN(CCC1)C=1C=NC(=CC=1)OC XKOYYBQSPAYHQL-GFCCVEGCSA-N 0.000 description 1
- XSXYEWFEZSYZCO-CQSZACIVSA-N FC1=CC=2C=3N(C(=NC=2C(=C1)OC)N)N=C(N=3)[C@H]1CN(CCC1)C=1C=NC(=CC=1)OC(C)C Chemical compound FC1=CC=2C=3N(C(=NC=2C(=C1)OC)N)N=C(N=3)[C@H]1CN(CCC1)C=1C=NC(=CC=1)OC(C)C XSXYEWFEZSYZCO-CQSZACIVSA-N 0.000 description 1
- JIQDXLXYVDIFTD-LLVKDONJSA-N FC1=CC=2C=3N(C(=NC=2C(=C1)OC)N)N=C(N=3)[C@H]1CN(CCC1)C=1C=NN(C=1)C Chemical compound FC1=CC=2C=3N(C(=NC=2C(=C1)OC)N)N=C(N=3)[C@H]1CN(CCC1)C=1C=NN(C=1)C JIQDXLXYVDIFTD-LLVKDONJSA-N 0.000 description 1
- OJTBEBLEYZUXJC-OAHLLOKOSA-N FC1=CC=2C=3N(C(=NC=2C=C1OC)N)N=C(N=3)[C@H]1CN(CCC1)C=1C(=NN(C=1)C1CCOCC1)C Chemical compound FC1=CC=2C=3N(C(=NC=2C=C1OC)N)N=C(N=3)[C@H]1CN(CCC1)C=1C(=NN(C=1)C1CCOCC1)C OJTBEBLEYZUXJC-OAHLLOKOSA-N 0.000 description 1
- QFKPQQYALWARTH-GFCCVEGCSA-N FC1=CC=2C=3N(C(=NC=2C=C1OC)N)N=C(N=3)[C@H]1CN(CCC1)C=1C=NC(=CC=1)OC Chemical compound FC1=CC=2C=3N(C(=NC=2C=C1OC)N)N=C(N=3)[C@H]1CN(CCC1)C=1C=NC(=CC=1)OC QFKPQQYALWARTH-GFCCVEGCSA-N 0.000 description 1
- KLVNBQMZYXNYNR-CQSZACIVSA-N FC1=CC=2C=3N(C(=NC=2C=C1OC)N)N=C(N=3)[C@H]1CN(CCC1)C=1C=NC(=CC=1)OC(C)C Chemical compound FC1=CC=2C=3N(C(=NC=2C=C1OC)N)N=C(N=3)[C@H]1CN(CCC1)C=1C=NC(=CC=1)OC(C)C KLVNBQMZYXNYNR-CQSZACIVSA-N 0.000 description 1
- UZIRZHILTUYBIB-LLVKDONJSA-N FC1=CC=2C=3N(C(=NC=2C=C1OC)N)N=C(N=3)[C@H]1CN(CCC1)C=1C=NN(C=1)C Chemical compound FC1=CC=2C=3N(C(=NC=2C=C1OC)N)N=C(N=3)[C@H]1CN(CCC1)C=1C=NN(C=1)C UZIRZHILTUYBIB-LLVKDONJSA-N 0.000 description 1
- ANHNYLNUIMBONU-CYBMUJFWSA-N FC1=CC=2C=3N(C(=NC=2C=C1OC)N)N=C(N=3)[C@H]1CN(CCC1)C=1C=NN(C=1)C(C)C Chemical compound FC1=CC=2C=3N(C(=NC=2C=C1OC)N)N=C(N=3)[C@H]1CN(CCC1)C=1C=NN(C=1)C(C)C ANHNYLNUIMBONU-CYBMUJFWSA-N 0.000 description 1
- YRBJQIQKBPRZSG-LLVKDONJSA-N FC1=CC=2C=3N(C(=NC=2C=C1OC)N)N=C(N=3)[C@H]1CN(CCC1)C=1C=NN(C=1)CC(F)(F)F Chemical compound FC1=CC=2C=3N(C(=NC=2C=C1OC)N)N=C(N=3)[C@H]1CN(CCC1)C=1C=NN(C=1)CC(F)(F)F YRBJQIQKBPRZSG-LLVKDONJSA-N 0.000 description 1
- HDXWHNOVVVXTJQ-SNVBAGLBSA-N FC1=CC=2C=3N(C(=NC=2C=C1OC)N)N=C(N=3)[C@H]1CN(CCC1)C=1N=NN(C=1)C Chemical compound FC1=CC=2C=3N(C(=NC=2C=C1OC)N)N=C(N=3)[C@H]1CN(CCC1)C=1N=NN(C=1)C HDXWHNOVVVXTJQ-SNVBAGLBSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 1
- 229940123414 Folate antagonist Drugs 0.000 description 1
- 206010017533 Fungal infection Diseases 0.000 description 1
- 102000003688 G-Protein-Coupled Receptors Human genes 0.000 description 1
- 108090000045 G-Protein-Coupled Receptors Proteins 0.000 description 1
- 230000005526 G1 to G0 transition Effects 0.000 description 1
- 206010017577 Gait disturbance Diseases 0.000 description 1
- 208000010412 Glaucoma Diseases 0.000 description 1
- 239000000579 Gonadotropin-Releasing Hormone Substances 0.000 description 1
- 108010069236 Goserelin Proteins 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- 208000017604 Hodgkin disease Diseases 0.000 description 1
- 208000021519 Hodgkin lymphoma Diseases 0.000 description 1
- 208000010747 Hodgkins lymphoma Diseases 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101000834898 Homo sapiens Alpha-synuclein Proteins 0.000 description 1
- 101000713106 Homo sapiens C-C motif chemokine 19 Proteins 0.000 description 1
- 101100407305 Homo sapiens CD274 gene Proteins 0.000 description 1
- 101001019455 Homo sapiens ICOS ligand Proteins 0.000 description 1
- 101100407307 Homo sapiens PDCD1LG2 gene Proteins 0.000 description 1
- 101001012157 Homo sapiens Receptor tyrosine-protein kinase erbB-2 Proteins 0.000 description 1
- 101000652359 Homo sapiens Spermatogenesis-associated protein 2 Proteins 0.000 description 1
- 101000611183 Homo sapiens Tumor necrosis factor Proteins 0.000 description 1
- 241000701085 Human alphaherpesvirus 3 Species 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical class Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- DOMWKUIIPQCAJU-LJHIYBGHSA-N Hydroxyprogesterone caproate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(C)=O)(OC(=O)CCCCC)[C@@]1(C)CC2 DOMWKUIIPQCAJU-LJHIYBGHSA-N 0.000 description 1
- VSNHCAURESNICA-UHFFFAOYSA-N Hydroxyurea Chemical compound NC(=O)NO VSNHCAURESNICA-UHFFFAOYSA-N 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 208000006083 Hypokinesia Diseases 0.000 description 1
- 102100034980 ICOS ligand Human genes 0.000 description 1
- 238000004566 IR spectroscopy Methods 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 102000037982 Immune checkpoint proteins Human genes 0.000 description 1
- 108091008036 Immune checkpoint proteins Proteins 0.000 description 1
- 108060003951 Immunoglobulin Proteins 0.000 description 1
- 102000017727 Immunoglobulin Variable Region Human genes 0.000 description 1
- 108010067060 Immunoglobulin Variable Region Proteins 0.000 description 1
- 108010065805 Interleukin-12 Proteins 0.000 description 1
- 102000013462 Interleukin-12 Human genes 0.000 description 1
- 102000003816 Interleukin-13 Human genes 0.000 description 1
- 108090000176 Interleukin-13 Proteins 0.000 description 1
- 108090000172 Interleukin-15 Proteins 0.000 description 1
- 108090000171 Interleukin-18 Proteins 0.000 description 1
- 102000000588 Interleukin-2 Human genes 0.000 description 1
- 108010002350 Interleukin-2 Proteins 0.000 description 1
- 108010002386 Interleukin-3 Proteins 0.000 description 1
- 102000000646 Interleukin-3 Human genes 0.000 description 1
- 108090000978 Interleukin-4 Proteins 0.000 description 1
- 208000007766 Kaposi sarcoma Diseases 0.000 description 1
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 1
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 1
- 229930182821 L-proline Natural products 0.000 description 1
- 102000017578 LAG3 Human genes 0.000 description 1
- 101150030213 Lag3 gene Proteins 0.000 description 1
- 108010000817 Leuprolide Proteins 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- GQYIWUVLTXOXAJ-UHFFFAOYSA-N Lomustine Chemical compound ClCCN(N=O)C(=O)NC1CCCCC1 GQYIWUVLTXOXAJ-UHFFFAOYSA-N 0.000 description 1
- 102000009151 Luteinizing Hormone Human genes 0.000 description 1
- 108010073521 Luteinizing Hormone Proteins 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 108010046938 Macrophage Colony-Stimulating Factor Proteins 0.000 description 1
- 102000007651 Macrophage Colony-Stimulating Factor Human genes 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 1
- 208000002030 Merkel cell carcinoma Diseases 0.000 description 1
- FQISKWAFAHGMGT-SGJOWKDISA-M Methylprednisolone sodium succinate Chemical compound [Na+].C([C@@]12C)=CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2[C@@H](O)C[C@]2(C)[C@@](O)(C(=O)COC(=O)CCC([O-])=O)CC[C@H]21 FQISKWAFAHGMGT-SGJOWKDISA-M 0.000 description 1
- GCKMFJBGXUYNAG-HLXURNFRSA-N Methyltestosterone Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@](C)(O)[C@@]1(C)CC2 GCKMFJBGXUYNAG-HLXURNFRSA-N 0.000 description 1
- 229930192392 Mitomycin Natural products 0.000 description 1
- 208000031888 Mycoses Diseases 0.000 description 1
- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 description 1
- FWINPYBBJUUTDO-UHFFFAOYSA-N N(N)C(=O)C1CCC(N(C1)C(=O)OC(C)(C)C)C Chemical compound N(N)C(=O)C1CCC(N(C1)C(=O)OC(C)(C)C)C FWINPYBBJUUTDO-UHFFFAOYSA-N 0.000 description 1
- WJRQNNBDGLGGBJ-UHFFFAOYSA-N N-[(2,4-dimethoxyphenyl)methyl]-2-(1,1-dioxo-1,4-thiazinan-2-yl)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-5-amine Chemical compound COC1=C(CNC2=NC=3C=C(C(=CC=3C=3N2N=C(N=3)C2CNCCS2(=O)=O)F)OC)C=CC(=C1)OC WJRQNNBDGLGGBJ-UHFFFAOYSA-N 0.000 description 1
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 description 1
- UEEJHVSXFDXPFK-UHFFFAOYSA-N N-dimethylaminoethanol Chemical compound CN(C)CCO UEEJHVSXFDXPFK-UHFFFAOYSA-N 0.000 description 1
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical class CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
- OJPSBHKVOGORGV-UHFFFAOYSA-N N1(CC(CCCC1)C(=O)OC)C(=O)OC(C)(C)C Chemical compound N1(CC(CCCC1)C(=O)OC)C(=O)OC(C)(C)C OJPSBHKVOGORGV-UHFFFAOYSA-N 0.000 description 1
- KZHNXGVTHZRFCM-UHFFFAOYSA-N N1CC(CCCC1)C1=NN2C(=NC=3C(=CC(=CC=3C2=N1)F)OC)NCC1=C(C=C(C=C1)OC)OC Chemical compound N1CC(CCCC1)C1=NN2C(=NC=3C(=CC(=CC=3C2=N1)F)OC)NCC1=C(C=C(C=C1)OC)OC KZHNXGVTHZRFCM-UHFFFAOYSA-N 0.000 description 1
- VLIVFOCFBNWZBR-GFCCVEGCSA-N NC1=NC=2C(=CC(=CC=2C=2N1N=C(N=2)[C@H]1CN(CCC1)C1=NN(C=N1)CC(C)(O)C)F)OC Chemical compound NC1=NC=2C(=CC(=CC=2C=2N1N=C(N=2)[C@H]1CN(CCC1)C1=NN(C=N1)CC(C)(O)C)F)OC VLIVFOCFBNWZBR-GFCCVEGCSA-N 0.000 description 1
- LRCWNGOOEQWGGB-CYBMUJFWSA-N NC1=NC=2C(=CC(=CC=2C=2N1N=C(N=2)[C@H]1CN(CCC1)C=1C=NN(C=1)C(CO)(C)C)F)OC Chemical compound NC1=NC=2C(=CC(=CC=2C=2N1N=C(N=2)[C@H]1CN(CCC1)C=1C=NN(C=1)C(CO)(C)C)F)OC LRCWNGOOEQWGGB-CYBMUJFWSA-N 0.000 description 1
- RLUHDYHHIOMUAN-CYBMUJFWSA-N NC1=NC=2C(=CC(=CC=2C=2N1N=C(N=2)[C@H]1CN(CCC1)C=1C=NN(C=1)CC(C)(O)C)F)OC Chemical compound NC1=NC=2C(=CC(=CC=2C=2N1N=C(N=2)[C@H]1CN(CCC1)C=1C=NN(C=1)CC(C)(O)C)F)OC RLUHDYHHIOMUAN-CYBMUJFWSA-N 0.000 description 1
- DXZOINLKNONFCH-CYBMUJFWSA-N NC1=NC=2C=C(C(=CC=2C=2N1N=C(N=2)[C@H]1CN(CCC1)C1=NN(C(=N1)C)CC(C)(O)C)F)OC Chemical compound NC1=NC=2C=C(C(=CC=2C=2N1N=C(N=2)[C@H]1CN(CCC1)C1=NN(C(=N1)C)CC(C)(O)C)F)OC DXZOINLKNONFCH-CYBMUJFWSA-N 0.000 description 1
- BHTKTSYNQIBIHO-CQSZACIVSA-N NC1=NC=2C=C(C(=CC=2C=2N1N=C(N=2)[C@H]1CN(CCC1)C=1C(=NN(C=1)C(CO)(C)C)C)F)OC Chemical compound NC1=NC=2C=C(C(=CC=2C=2N1N=C(N=2)[C@H]1CN(CCC1)C=1C(=NN(C=1)C(CO)(C)C)C)F)OC BHTKTSYNQIBIHO-CQSZACIVSA-N 0.000 description 1
- ZCTMXDGOOPVGPI-CQSZACIVSA-N NC1=NC=2C=C(C(=CC=2C=2N1N=C(N=2)[C@H]1CN(CCC1)C=1C(=NN(C=1)CC(C)(O)C)C)F)OC Chemical compound NC1=NC=2C=C(C(=CC=2C=2N1N=C(N=2)[C@H]1CN(CCC1)C=1C(=NN(C=1)CC(C)(O)C)C)F)OC ZCTMXDGOOPVGPI-CQSZACIVSA-N 0.000 description 1
- VFKMIEMLJHHTFK-OAHLLOKOSA-N NC1=NC=2C=C(C(=CC=2C=2N1N=C(N=2)[C@H]1CN(CCC1)C=1C(=NN(C=1)CC(C)(O)C)C1CC1)F)OC Chemical compound NC1=NC=2C=C(C(=CC=2C=2N1N=C(N=2)[C@H]1CN(CCC1)C=1C(=NN(C=1)CC(C)(O)C)C1CC1)F)OC VFKMIEMLJHHTFK-OAHLLOKOSA-N 0.000 description 1
- HEUNQDDHZNHOHE-GFCCVEGCSA-N NC1=NC=2C=C(C(=CC=2C=2N1N=C(N=2)[C@H]1CN(CCC1)C=1C=C(C(N(C=1)C(F)F)=O)C)F)OC Chemical compound NC1=NC=2C=C(C(=CC=2C=2N1N=C(N=2)[C@H]1CN(CCC1)C=1C=C(C(N(C=1)C(F)F)=O)C)F)OC HEUNQDDHZNHOHE-GFCCVEGCSA-N 0.000 description 1
- GMYITRKBDLPKDN-CQSZACIVSA-N NC1=NC=2C=C(C(=CC=2C=2N1N=C(N=2)[C@H]1CN(CCC1)C=1C=NN(C=1)CC1(CCC1)O)F)OC Chemical compound NC1=NC=2C=C(C(=CC=2C=2N1N=C(N=2)[C@H]1CN(CCC1)C=1C=NN(C=1)CC1(CCC1)O)F)OC GMYITRKBDLPKDN-CQSZACIVSA-N 0.000 description 1
- PATGJNBEXAFFSZ-CQSZACIVSA-N NC1=NC=2C=C(C(=CC=2C=2N1N=C(N=2)[C@H]1CN(CCC1)C=1C=NN(C=1)CCC(C)(O)C)F)OC Chemical compound NC1=NC=2C=C(C(=CC=2C=2N1N=C(N=2)[C@H]1CN(CCC1)C=1C=NN(C=1)CCC(C)(O)C)F)OC PATGJNBEXAFFSZ-CQSZACIVSA-N 0.000 description 1
- 206010029266 Neuroendocrine carcinoma of the skin Diseases 0.000 description 1
- BVWYBAPBRQKXPX-UHFFFAOYSA-N O1C(CCCC1)OC1(CC1)CN1N=CC(=C1)N Chemical compound O1C(CCCC1)OC1(CC1)CN1N=CC(=C1)N BVWYBAPBRQKXPX-UHFFFAOYSA-N 0.000 description 1
- YCVKSYDPWFHEKM-UHFFFAOYSA-N O1CCOC11CCC(CC1)N1N=CC(=C1)N1CC(CCC1C)C(=O)OC Chemical compound O1CCOC11CCC(CC1)N1N=CC(=C1)N1CC(CCC1C)C(=O)OC YCVKSYDPWFHEKM-UHFFFAOYSA-N 0.000 description 1
- VNJSPYVGZWXTCT-UHFFFAOYSA-N OC(CN1N=CC(=C1)N1CC(CCC1C)C(=O)NN)(CO)C Chemical compound OC(CN1N=CC(=C1)N1CC(CCC1C)C(=O)NN)(CO)C VNJSPYVGZWXTCT-UHFFFAOYSA-N 0.000 description 1
- 239000012425 OXONE® Substances 0.000 description 1
- 208000001388 Opportunistic Infections Diseases 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 229910019213 POCl3 Inorganic materials 0.000 description 1
- 229930012538 Paclitaxel Natural products 0.000 description 1
- 208000030852 Parasitic disease Diseases 0.000 description 1
- NFHFRUOZVGFOOS-UHFFFAOYSA-N Pd(PPh3)4 Substances [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 1
- 208000037581 Persistent Infection Diseases 0.000 description 1
- 102100033616 Phospholipid-transporting ATPase ABCA1 Human genes 0.000 description 1
- 101710205202 Phospholipid-transporting ATPase ABCA1 Proteins 0.000 description 1
- 101710094000 Programmed cell death 1 ligand 1 Proteins 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Chemical class CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 1
- 208000028017 Psychotic disease Diseases 0.000 description 1
- 101710100968 Receptor tyrosine-protein kinase erbB-2 Proteins 0.000 description 1
- 208000001647 Renal Insufficiency Diseases 0.000 description 1
- 208000006265 Renal cell carcinoma Diseases 0.000 description 1
- 229940127395 Ribonucleotide Reductase Inhibitors Drugs 0.000 description 1
- PYMYPHUHKUWMLA-LMVFSUKVSA-N Ribose Natural products OC[C@@H](O)[C@@H](O)[C@@H](O)C=O PYMYPHUHKUWMLA-LMVFSUKVSA-N 0.000 description 1
- 206010039966 Senile dementia Diseases 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 101000857870 Squalus acanthias Gonadoliberin Proteins 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- 208000003734 Supraventricular Tachycardia Diseases 0.000 description 1
- 230000006044 T cell activation Effects 0.000 description 1
- 230000006052 T cell proliferation Effects 0.000 description 1
- 108091008874 T cell receptors Proteins 0.000 description 1
- 230000005867 T cell response Effects 0.000 description 1
- 206010043118 Tardive Dyskinesia Diseases 0.000 description 1
- 208000033133 Testicular seminomatous germ cell tumor Diseases 0.000 description 1
- PDMMFKSKQVNJMI-BLQWBTBKSA-N Testosterone propionate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](OC(=O)CC)[C@@]1(C)CC2 PDMMFKSKQVNJMI-BLQWBTBKSA-N 0.000 description 1
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 description 1
- FOCVUCIESVLUNU-UHFFFAOYSA-N Thiotepa Chemical compound C1CN1P(N1CC1)(=S)N1CC1 FOCVUCIESVLUNU-UHFFFAOYSA-N 0.000 description 1
- 208000024770 Thyroid neoplasm Diseases 0.000 description 1
- 239000000365 Topoisomerase I Inhibitor Substances 0.000 description 1
- 239000000317 Topoisomerase II Inhibitor Substances 0.000 description 1
- 206010044565 Tremor Diseases 0.000 description 1
- 102000004243 Tubulin Human genes 0.000 description 1
- 108090000704 Tubulin Proteins 0.000 description 1
- 206010053613 Type IV hypersensitivity reaction Diseases 0.000 description 1
- 102100022596 Tyrosine-protein kinase ABL1 Human genes 0.000 description 1
- JXLYSJRDGCGARV-WWYNWVTFSA-N Vinblastine Natural products O=C(O[C@H]1[C@](O)(C(=O)OC)[C@@H]2N(C)c3c(cc(c(OC)c3)[C@]3(C(=O)OC)c4[nH]c5c(c4CCN4C[C@](O)(CC)C[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C JXLYSJRDGCGARV-WWYNWVTFSA-N 0.000 description 1
- 239000002250 absorbent Substances 0.000 description 1
- 230000002745 absorbent Effects 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- 150000008043 acidic salts Chemical class 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- YBCVMFKXIKNREZ-UHFFFAOYSA-N acoh acetic acid Chemical compound CC(O)=O.CC(O)=O YBCVMFKXIKNREZ-UHFFFAOYSA-N 0.000 description 1
- RJURFGZVJUQBHK-IIXSONLDSA-N actinomycin D Chemical compound C[C@H]1OC(=O)[C@H](C(C)C)N(C)C(=O)CN(C)C(=O)[C@@H]2CCCN2C(=O)[C@@H](C(C)C)NC(=O)[C@H]1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)N[C@@H]4C(=O)N[C@@H](C(N5CCC[C@H]5C(=O)N(C)CC(=O)N(C)[C@@H](C(C)C)C(=O)O[C@@H]4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-IIXSONLDSA-N 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 description 1
- YKIOKAURTKXMSB-UHFFFAOYSA-N adams's catalyst Chemical compound O=[Pt]=O YKIOKAURTKXMSB-UHFFFAOYSA-N 0.000 description 1
- 229960000643 adenine Drugs 0.000 description 1
- UDMBCSSLTHHNCD-KQYNXXCUSA-N adenosine 5'-monophosphate Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@H]1O UDMBCSSLTHHNCD-KQYNXXCUSA-N 0.000 description 1
- LNQVTSROQXJCDD-UHFFFAOYSA-N adenosine monophosphate Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(CO)C(OP(O)(O)=O)C1O LNQVTSROQXJCDD-UHFFFAOYSA-N 0.000 description 1
- 102000030621 adenylate cyclase Human genes 0.000 description 1
- 108060000200 adenylate cyclase Proteins 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- WNLRTRBMVRJNCN-UHFFFAOYSA-N adipic acid Chemical class OC(=O)CCCCC(O)=O WNLRTRBMVRJNCN-UHFFFAOYSA-N 0.000 description 1
- 230000001919 adrenal effect Effects 0.000 description 1
- 210000004100 adrenal gland Anatomy 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- HMFHBZSHGGEWLO-UHFFFAOYSA-N alpha-D-Furanose-Ribose Natural products OCC1OC(O)C(O)C1O HMFHBZSHGGEWLO-UHFFFAOYSA-N 0.000 description 1
- 229960000473 altretamine Drugs 0.000 description 1
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical class [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 description 1
- 229940024606 amino acid Drugs 0.000 description 1
- 150000005415 aminobenzoic acids Chemical class 0.000 description 1
- 229960003437 aminoglutethimide Drugs 0.000 description 1
- ROBVIMPUHSLWNV-UHFFFAOYSA-N aminoglutethimide Chemical compound C=1C=C(N)C=CC=1C1(CC)CCC(=O)NC1=O ROBVIMPUHSLWNV-UHFFFAOYSA-N 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 229960001220 amsacrine Drugs 0.000 description 1
- XCPGHVQEEXUHNC-UHFFFAOYSA-N amsacrine Chemical compound COC1=CC(NS(C)(=O)=O)=CC=C1NC1=C(C=CC=C2)C2=NC2=CC=CC=C12 XCPGHVQEEXUHNC-UHFFFAOYSA-N 0.000 description 1
- 239000003098 androgen Substances 0.000 description 1
- 229940030486 androgens Drugs 0.000 description 1
- 239000002870 angiogenesis inducing agent Substances 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- 229940045799 anthracyclines and related substance Drugs 0.000 description 1
- 230000001430 anti-depressive effect Effects 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 230000036436 anti-hiv Effects 0.000 description 1
- 230000003388 anti-hormonal effect Effects 0.000 description 1
- 230000003622 anti-hsv Effects 0.000 description 1
- 230000000340 anti-metabolite Effects 0.000 description 1
- 239000012296 anti-solvent Substances 0.000 description 1
- 239000000051 antiandrogen Substances 0.000 description 1
- 239000003416 antiarrhythmic agent Substances 0.000 description 1
- 239000000935 antidepressant agent Substances 0.000 description 1
- 229940005513 antidepressants Drugs 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 229940100197 antimetabolite Drugs 0.000 description 1
- 239000002256 antimetabolite Substances 0.000 description 1
- 229940045719 antineoplastic alkylating agent nitrosoureas Drugs 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 150000001499 aryl bromides Chemical class 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 125000003289 ascorbyl group Chemical class [H]O[C@@]([H])(C([H])([H])O*)[C@@]1([H])OC(=O)C(O*)=C1O* 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-L aspartate group Chemical class N[C@@H](CC(=O)[O-])C(=O)[O-] CKLJMWTZIZZHCS-REOHCLBHSA-L 0.000 description 1
- 229960002756 azacitidine Drugs 0.000 description 1
- 125000005334 azaindolyl group Chemical group N1N=C(C2=CC=CC=C12)* 0.000 description 1
- VSRXQHXAPYXROS-UHFFFAOYSA-N azanide;cyclobutane-1,1-dicarboxylic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OC(=O)C1(C(O)=O)CCC1 VSRXQHXAPYXROS-UHFFFAOYSA-N 0.000 description 1
- 150000001541 aziridines Chemical class 0.000 description 1
- 210000003719 b-lymphocyte Anatomy 0.000 description 1
- 210000004227 basal ganglia Anatomy 0.000 description 1
- 239000011324 bead Substances 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical class OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 125000005513 benzoazaindolyl group Chemical group 0.000 description 1
- 125000004601 benzofurazanyl group Chemical group N1=C2C(=NO1)C(=CC=C2)* 0.000 description 1
- 150000001558 benzoic acid derivatives Chemical class 0.000 description 1
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 125000003180 beta-lactone group Chemical group 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 239000012472 biological sample Substances 0.000 description 1
- AZWXAPCAJCYGIA-UHFFFAOYSA-N bis(2-methylpropyl)alumane Chemical compound CC(C)C[AlH]CC(C)C AZWXAPCAJCYGIA-UHFFFAOYSA-N 0.000 description 1
- IPWKHHSGDUIRAH-UHFFFAOYSA-N bis(pinacolato)diboron Chemical compound O1C(C)(C)C(C)(C)OB1B1OC(C)(C)C(C)(C)O1 IPWKHHSGDUIRAH-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M bisulphate group Chemical group S([O-])(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- 229960001561 bleomycin Drugs 0.000 description 1
- OYVAGSVQBOHSSS-UAPAGMARSA-O bleomycin A2 Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCC[S+](C)C)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C OYVAGSVQBOHSSS-UAPAGMARSA-O 0.000 description 1
- 238000011243 body radiation therapy Methods 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 229910000085 borane Inorganic materials 0.000 description 1
- 150000001642 boronic acid derivatives Chemical class 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 230000005587 bubbling Effects 0.000 description 1
- 150000004648 butanoic acid derivatives Chemical class 0.000 description 1
- ZTQSAGDEMFDKMZ-UHFFFAOYSA-N butyric aldehyde Natural products CCCC=O ZTQSAGDEMFDKMZ-UHFFFAOYSA-N 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- MIOPJNTWMNEORI-UHFFFAOYSA-N camphorsulfonic acid Chemical class C1CC2(CS(O)(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-UHFFFAOYSA-N 0.000 description 1
- 229940022399 cancer vaccine Drugs 0.000 description 1
- 238000009566 cancer vaccine Methods 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 229960004562 carboplatin Drugs 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 229960005243 carmustine Drugs 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000022131 cell cycle Effects 0.000 description 1
- 208000015114 central nervous system disease Diseases 0.000 description 1
- 210000003679 cervix uteri Anatomy 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 229960004630 chlorambucil Drugs 0.000 description 1
- JCKYGMPEJWAADB-UHFFFAOYSA-N chlorambucil Chemical compound OC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 JCKYGMPEJWAADB-UHFFFAOYSA-N 0.000 description 1
- JWMLCCRPDOIBAV-UHFFFAOYSA-N chloro(methylsulfanyl)methane Chemical compound CSCCl JWMLCCRPDOIBAV-UHFFFAOYSA-N 0.000 description 1
- BFPSDSIWYFKGBC-UHFFFAOYSA-N chlorotrianisene Chemical compound C1=CC(OC)=CC=C1C(Cl)=C(C=1C=CC(OC)=CC=1)C1=CC=C(OC)C=C1 BFPSDSIWYFKGBC-UHFFFAOYSA-N 0.000 description 1
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 1
- 229960001231 choline Drugs 0.000 description 1
- 229960004316 cisplatin Drugs 0.000 description 1
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 1
- 150000001860 citric acid derivatives Chemical class 0.000 description 1
- FCEOGYWNOSBEPV-FDGPNNRMSA-N cobalt;(z)-4-hydroxypent-3-en-2-one Chemical compound [Co].C\C(O)=C\C(C)=O.C\C(O)=C\C(C)=O FCEOGYWNOSBEPV-FDGPNNRMSA-N 0.000 description 1
- 230000003920 cognitive function Effects 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 229940035811 conjugated estrogen Drugs 0.000 description 1
- 210000002808 connective tissue Anatomy 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- DOBRDRYODQBAMW-UHFFFAOYSA-N copper(i) cyanide Chemical compound [Cu+].N#[C-] DOBRDRYODQBAMW-UHFFFAOYSA-N 0.000 description 1
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 239000003246 corticosteroid Substances 0.000 description 1
- 229960001334 corticosteroids Drugs 0.000 description 1
- 208000017763 cutaneous neuroendocrine carcinoma Diseases 0.000 description 1
- 125000000392 cycloalkenyl group Chemical group 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 229960004397 cyclophosphamide Drugs 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 229960000684 cytarabine Drugs 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 229960003901 dacarbazine Drugs 0.000 description 1
- 229960000640 dactinomycin Drugs 0.000 description 1
- VRLDVERQJMEPIF-UHFFFAOYSA-N dbdmh Chemical compound CC1(C)N(Br)C(=O)N(Br)C1=O VRLDVERQJMEPIF-UHFFFAOYSA-N 0.000 description 1
- DEZRYPDIMOWBDS-UHFFFAOYSA-N dcm dichloromethane Chemical compound ClCCl.ClCCl DEZRYPDIMOWBDS-UHFFFAOYSA-N 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000006735 deficit Effects 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 125000000422 delta-lactone group Chemical group 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 229960003957 dexamethasone Drugs 0.000 description 1
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 1
- 150000008050 dialkyl sulfates Chemical class 0.000 description 1
- RGLYKWWBQGJZGM-ISLYRVAYSA-N diethylstilbestrol Chemical compound C=1C=C(O)C=CC=1C(/CC)=C(\CC)C1=CC=C(O)C=C1 RGLYKWWBQGJZGM-ISLYRVAYSA-N 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000012972 dimethylethanolamine Substances 0.000 description 1
- UXGNZZKBCMGWAZ-UHFFFAOYSA-N dimethylformamide dmf Chemical compound CN(C)C=O.CN(C)C=O UXGNZZKBCMGWAZ-UHFFFAOYSA-N 0.000 description 1
- GAFRWLVTHPVQGK-UHFFFAOYSA-N dipentyl sulfate Chemical class CCCCCOS(=O)(=O)OCCCCC GAFRWLVTHPVQGK-UHFFFAOYSA-N 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- SACNIGZYDTUHKB-UHFFFAOYSA-N ditert-butyl-[2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphane Chemical compound CC(C)C1=CC(C(C)C)=CC(C(C)C)=C1C1=CC=CC=C1P(C(C)(C)C)C(C)(C)C SACNIGZYDTUHKB-UHFFFAOYSA-N 0.000 description 1
- CETRZFQIITUQQL-UHFFFAOYSA-N dmso dimethylsulfoxide Chemical compound CS(C)=O.CS(C)=O CETRZFQIITUQQL-UHFFFAOYSA-N 0.000 description 1
- 229960003668 docetaxel Drugs 0.000 description 1
- 125000003438 dodecyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- MOTZDAYCYVMXPC-UHFFFAOYSA-N dodecyl hydrogen sulfate Chemical class CCCCCCCCCCCCOS(O)(=O)=O MOTZDAYCYVMXPC-UHFFFAOYSA-N 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 238000009510 drug design Methods 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 208000010118 dystonia Diseases 0.000 description 1
- 210000003162 effector t lymphocyte Anatomy 0.000 description 1
- 238000000132 electrospray ionisation Methods 0.000 description 1
- 238000003821 enantio-separation Methods 0.000 description 1
- 238000005538 encapsulation Methods 0.000 description 1
- 239000006274 endogenous ligand Substances 0.000 description 1
- 210000004696 endometrium Anatomy 0.000 description 1
- 210000002889 endothelial cell Anatomy 0.000 description 1
- 150000002085 enols Chemical class 0.000 description 1
- 229960001904 epirubicin Drugs 0.000 description 1
- 150000003883 epothilone derivatives Chemical class 0.000 description 1
- 230000008029 eradication Effects 0.000 description 1
- 210000003238 esophagus Anatomy 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- FRPJXPJMRWBBIH-RBRWEJTLSA-N estramustine Chemical compound ClCCN(CCCl)C(=O)OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 FRPJXPJMRWBBIH-RBRWEJTLSA-N 0.000 description 1
- 229960001842 estramustine Drugs 0.000 description 1
- 229940011871 estrogen Drugs 0.000 description 1
- 239000000262 estrogen Substances 0.000 description 1
- OLAMWIPURJGSKE-UHFFFAOYSA-N et2o diethylether Chemical compound CCOCC.CCOCC OLAMWIPURJGSKE-UHFFFAOYSA-N 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-N ethanesulfonic acid Chemical class CCS(O)(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-N 0.000 description 1
- OCLXJTCGWSSVOE-UHFFFAOYSA-N ethanol etoh Chemical compound CCO.CCO OCLXJTCGWSSVOE-UHFFFAOYSA-N 0.000 description 1
- 229960002568 ethinylestradiol Drugs 0.000 description 1
- XIWBSOUNZWSFKU-SSDOTTSWSA-N ethyl (3r)-piperidine-3-carboxylate Chemical compound CCOC(=O)[C@@H]1CCCNC1 XIWBSOUNZWSFKU-SSDOTTSWSA-N 0.000 description 1
- IOLQWGVDEFWYNP-UHFFFAOYSA-N ethyl 2-bromo-2-methylpropanoate Chemical compound CCOC(=O)C(C)(C)Br IOLQWGVDEFWYNP-UHFFFAOYSA-N 0.000 description 1
- FQTIYMRSUOADDK-UHFFFAOYSA-N ethyl 3-bromopropanoate Chemical compound CCOC(=O)CCBr FQTIYMRSUOADDK-UHFFFAOYSA-N 0.000 description 1
- OJCSPXHYDFONPU-UHFFFAOYSA-N etoac etoac Chemical compound CCOC(C)=O.CCOC(C)=O OJCSPXHYDFONPU-UHFFFAOYSA-N 0.000 description 1
- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 description 1
- 229960005420 etoposide Drugs 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 229960000961 floxuridine Drugs 0.000 description 1
- 108700014844 flt3 ligand Proteins 0.000 description 1
- RFHAOTPXVQNOHP-UHFFFAOYSA-N fluconazole Chemical compound C1=NC=NN1CC(C=1C(=CC(F)=CC=1)F)(O)CN1C=NC=N1 RFHAOTPXVQNOHP-UHFFFAOYSA-N 0.000 description 1
- 229960004884 fluconazole Drugs 0.000 description 1
- 229960000390 fludarabine Drugs 0.000 description 1
- GIUYCYHIANZCFB-FJFJXFQQSA-N fludarabine phosphate Chemical compound C1=NC=2C(N)=NC(F)=NC=2N1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@@H]1O GIUYCYHIANZCFB-FJFJXFQQSA-N 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229960002949 fluorouracil Drugs 0.000 description 1
- YLRFCQOZQXIBAB-RBZZARIASA-N fluoxymesterone Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1CC[C@](C)(O)[C@@]1(C)C[C@@H]2O YLRFCQOZQXIBAB-RBZZARIASA-N 0.000 description 1
- 229960001751 fluoxymesterone Drugs 0.000 description 1
- 229960002074 flutamide Drugs 0.000 description 1
- MKXKFYHWDHIYRV-UHFFFAOYSA-N flutamide Chemical compound CC(C)C(=O)NC1=CC=C([N+]([O-])=O)C(C(F)(F)F)=C1 MKXKFYHWDHIYRV-UHFFFAOYSA-N 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-L fumarate(2-) Chemical class [O-]C(=O)\C=C\C([O-])=O VZCYOOQTPOCHFL-OWOJBTEDSA-L 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 125000000457 gamma-lactone group Chemical group 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 208000010749 gastric carcinoma Diseases 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 229960005277 gemcitabine Drugs 0.000 description 1
- SDUQYLNIPVEERB-QPPQHZFASA-N gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 description 1
- 208000005017 glioblastoma Diseases 0.000 description 1
- 150000002315 glycerophosphates Chemical class 0.000 description 1
- XLXSAKCOAKORKW-AQJXLSMYSA-N gonadorelin Chemical compound C([C@@H](C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)NCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 XLXSAKCOAKORKW-AQJXLSMYSA-N 0.000 description 1
- 229940035638 gonadotropin-releasing hormone Drugs 0.000 description 1
- 229960003690 goserelin acetate Drugs 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 125000001188 haloalkyl group Chemical group 0.000 description 1
- 201000010536 head and neck cancer Diseases 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- MNWFXJYAOYHMED-UHFFFAOYSA-N heptanoic acid Chemical class CCCCCCC(O)=O MNWFXJYAOYHMED-UHFFFAOYSA-N 0.000 description 1
- UUVWYPNAQBNQJQ-UHFFFAOYSA-N hexamethylmelamine Chemical compound CN(C)C1=NC(N(C)C)=NC(N(C)C)=N1 UUVWYPNAQBNQJQ-UHFFFAOYSA-N 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical class CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 1
- 229940125697 hormonal agent Drugs 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 229940042795 hydrazides for tuberculosis treatment Drugs 0.000 description 1
- LRVRXTVCBXLPIU-UHFFFAOYSA-N hydrazinecarbonyl piperidine-1-carboxylate Chemical compound NNC(=O)OC(=O)N1CCCCC1 LRVRXTVCBXLPIU-UHFFFAOYSA-N 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical class I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 229960001330 hydroxycarbamide Drugs 0.000 description 1
- 229950000801 hydroxyprogesterone caproate Drugs 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 125000005945 imidazopyridyl group Chemical group 0.000 description 1
- 230000036737 immune function Effects 0.000 description 1
- 230000003832 immune regulation Effects 0.000 description 1
- 230000008629 immune suppression Effects 0.000 description 1
- 230000037451 immune surveillance Effects 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 208000026278 immune system disease Diseases 0.000 description 1
- 230000002163 immunogen Effects 0.000 description 1
- 102000018358 immunoglobulin Human genes 0.000 description 1
- 230000002584 immunomodulator Effects 0.000 description 1
- 230000001024 immunotherapeutic effect Effects 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 102000006639 indoleamine 2,3-dioxygenase Human genes 0.000 description 1
- 108020004201 indoleamine 2,3-dioxygenase Proteins 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 230000028709 inflammatory response Effects 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 229940102223 injectable solution Drugs 0.000 description 1
- 229940102213 injectable suspension Drugs 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 230000010354 integration Effects 0.000 description 1
- 230000002452 interceptive effect Effects 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- UWKQSNNFCGGAFS-XIFFEERXSA-N irinotecan Chemical compound C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 UWKQSNNFCGGAFS-XIFFEERXSA-N 0.000 description 1
- 229960004768 irinotecan Drugs 0.000 description 1
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical class OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
- 201000006370 kidney failure Diseases 0.000 description 1
- 229940043355 kinase inhibitor Drugs 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 150000003893 lactate salts Chemical class 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 210000000265 leukocyte Anatomy 0.000 description 1
- GFIJNRVAKGFPGQ-LIJARHBVSA-N leuprolide Chemical compound CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)CC1=CC=C(O)C=C1 GFIJNRVAKGFPGQ-LIJARHBVSA-N 0.000 description 1
- 229960004338 leuprorelin Drugs 0.000 description 1
- 239000012669 liquid formulation Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 230000033001 locomotion Effects 0.000 description 1
- 229960002247 lomustine Drugs 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 201000005249 lung adenocarcinoma Diseases 0.000 description 1
- 210000004924 lung microvascular endothelial cell Anatomy 0.000 description 1
- 229940040129 luteinizing hormone Drugs 0.000 description 1
- 210000004698 lymphocyte Anatomy 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- FRIJBUGBVQZNTB-UHFFFAOYSA-M magnesium;ethane;bromide Chemical compound [Mg+2].[Br-].[CH2-]C FRIJBUGBVQZNTB-UHFFFAOYSA-M 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 201000004792 malaria Diseases 0.000 description 1
- 150000002688 maleic acid derivatives Chemical class 0.000 description 1
- 230000036210 malignancy Effects 0.000 description 1
- 201000010893 malignant breast melanoma Diseases 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 229960004961 mechlorethamine Drugs 0.000 description 1
- HAWPXGHAZFHHAD-UHFFFAOYSA-N mechlorethamine Chemical compound ClCCN(C)CCCl HAWPXGHAZFHHAD-UHFFFAOYSA-N 0.000 description 1
- BCVXHSPFUWZLGQ-UHFFFAOYSA-N mecn acetonitrile Chemical compound CC#N.CC#N BCVXHSPFUWZLGQ-UHFFFAOYSA-N 0.000 description 1
- 229960004616 medroxyprogesterone Drugs 0.000 description 1
- PSGAAPLEWMOORI-PEINSRQWSA-N medroxyprogesterone acetate Chemical compound C([C@@]12C)CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2CC[C@]2(C)[C@@](OC(C)=O)(C(C)=O)CC[C@H]21 PSGAAPLEWMOORI-PEINSRQWSA-N 0.000 description 1
- 229960001786 megestrol Drugs 0.000 description 1
- RQZAXGRLVPAYTJ-GQFGMJRRSA-N megestrol acetate Chemical compound C1=C(C)C2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(C)=O)(OC(=O)C)[C@@]1(C)CC2 RQZAXGRLVPAYTJ-GQFGMJRRSA-N 0.000 description 1
- 229960001924 melphalan Drugs 0.000 description 1
- SGDBTWWWUNNDEQ-LBPRGKRZSA-N melphalan Chemical compound OC(=O)[C@@H](N)CC1=CC=C(N(CCCl)CCCl)C=C1 SGDBTWWWUNNDEQ-LBPRGKRZSA-N 0.000 description 1
- COTNUBDHGSIOTA-UHFFFAOYSA-N meoh methanol Chemical class OC.OC COTNUBDHGSIOTA-UHFFFAOYSA-N 0.000 description 1
- GLVAUDGFNGKCSF-UHFFFAOYSA-N mercaptopurine Chemical compound S=C1NC=NC2=C1NC=N2 GLVAUDGFNGKCSF-UHFFFAOYSA-N 0.000 description 1
- 229960001428 mercaptopurine Drugs 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- LVWZTYCIRDMTEY-UHFFFAOYSA-N metamizole Chemical compound O=C1C(N(CS(O)(=O)=O)C)=C(C)N(C)N1C1=CC=CC=C1 LVWZTYCIRDMTEY-UHFFFAOYSA-N 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-M methanesulfonate group Chemical class CS(=O)(=O)[O-] AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- BGPCMVNMLWHVQR-UHFFFAOYSA-N methyl 2-(4-bromo-3-methylpyrazol-1-yl)-2-methylpropanoate Chemical compound COC(=O)C(C)(C)N1C=C(Br)C(C)=N1 BGPCMVNMLWHVQR-UHFFFAOYSA-N 0.000 description 1
- CFTUQSLVERGMHL-UHFFFAOYSA-N methyl 2-(bromomethyl)prop-2-enoate Chemical compound COC(=O)C(=C)CBr CFTUQSLVERGMHL-UHFFFAOYSA-N 0.000 description 1
- PQUSVJVVRXWKDG-UHFFFAOYSA-N methyl 2-bromo-2-methylpropanoate Chemical compound COC(=O)C(C)(C)Br PQUSVJVVRXWKDG-UHFFFAOYSA-N 0.000 description 1
- JHYKOXJKJHTKTE-UHFFFAOYSA-N methyl 3-pyrrolidin-1-ylpropanoate Chemical compound COC(=O)CCN1CCCC1 JHYKOXJKJHTKTE-UHFFFAOYSA-N 0.000 description 1
- XMJHPCRAQCTCFT-UHFFFAOYSA-N methyl chloroformate Chemical compound COC(Cl)=O XMJHPCRAQCTCFT-UHFFFAOYSA-N 0.000 description 1
- 150000005451 methyl sulfates Chemical class 0.000 description 1
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 1
- 229960004584 methylprednisolone Drugs 0.000 description 1
- 229960001566 methyltestosterone Drugs 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000008185 minitablet Substances 0.000 description 1
- 229960004857 mitomycin Drugs 0.000 description 1
- 229960000350 mitotane Drugs 0.000 description 1
- 229960001156 mitoxantrone Drugs 0.000 description 1
- KKZJGLLVHKMTCM-UHFFFAOYSA-N mitoxantrone Chemical compound O=C1C2=C(O)C=CC(O)=C2C(=O)C2=C1C(NCCNCCO)=CC=C2NCCNCCO KKZJGLLVHKMTCM-UHFFFAOYSA-N 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 210000001616 monocyte Anatomy 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- 210000000214 mouth Anatomy 0.000 description 1
- 201000006417 multiple sclerosis Diseases 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 125000001421 myristyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- KVKFRMCSXWQSNT-UHFFFAOYSA-N n,n'-dimethylethane-1,2-diamine Chemical compound CNCCNC KVKFRMCSXWQSNT-UHFFFAOYSA-N 0.000 description 1
- PEECTLLHENGOKU-UHFFFAOYSA-N n,n-dimethylpyridin-4-amine Chemical compound CN(C)C1=CC=NC=C1.CN(C)C1=CC=NC=C1 PEECTLLHENGOKU-UHFFFAOYSA-N 0.000 description 1
- JFLWIOVDKRZVLU-UHFFFAOYSA-N n-(2-morpholin-4-ylethyl)-n'-propan-2-yloxamide Chemical compound CC(C)NC(=O)C(=O)NCCN1CCOCC1 JFLWIOVDKRZVLU-UHFFFAOYSA-N 0.000 description 1
- BLCLNMBMMGCOAS-UHFFFAOYSA-N n-[1-[[1-[[1-[[1-[[1-[[1-[[1-[2-[(carbamoylamino)carbamoyl]pyrrolidin-1-yl]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-[(2-methylpropan-2-yl)oxy]-1-oxopropan-2-yl]amino]-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]amin Chemical compound C1CCC(C(=O)NNC(N)=O)N1C(=O)C(CCCN=C(N)N)NC(=O)C(CC(C)C)NC(=O)C(COC(C)(C)C)NC(=O)C(NC(=O)C(CO)NC(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)C(CC=1NC=NC=1)NC(=O)C1NC(=O)CC1)CC1=CC=C(O)C=C1 BLCLNMBMMGCOAS-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- TXTHKGMZDDTZFD-UHFFFAOYSA-N n-cyclohexylaniline Chemical compound C1CCCCC1NC1=CC=CC=C1 TXTHKGMZDDTZFD-UHFFFAOYSA-N 0.000 description 1
- WOOWBQQQJXZGIE-UHFFFAOYSA-N n-ethyl-n-propan-2-ylpropan-2-amine Chemical compound CCN(C(C)C)C(C)C.CCN(C(C)C)C(C)C WOOWBQQQJXZGIE-UHFFFAOYSA-N 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 210000004160 naive b lymphocyte Anatomy 0.000 description 1
- 210000004296 naive t lymphocyte Anatomy 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-N naphthalene-2-sulfonic acid Chemical class C1=CC=CC2=CC(S(=O)(=O)O)=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 210000002850 nasal mucosa Anatomy 0.000 description 1
- 210000000822 natural killer cell Anatomy 0.000 description 1
- 210000003739 neck Anatomy 0.000 description 1
- 230000004770 neurodegeneration Effects 0.000 description 1
- 208000015122 neurodegenerative disease Diseases 0.000 description 1
- 239000002858 neurotransmitter agent Substances 0.000 description 1
- 150000002814 niacins Chemical class 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 150000002823 nitrates Chemical class 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 125000002868 norbornyl group Chemical group C12(CCC(CC1)C2)* 0.000 description 1
- 210000001331 nose Anatomy 0.000 description 1
- 239000002777 nucleoside Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000002611 ovarian Effects 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- 150000003891 oxalate salts Chemical class 0.000 description 1
- DWAFYCQODLXJNR-BNTLRKBRSA-L oxaliplatin Chemical compound O1C(=O)C(=O)O[Pt]11N[C@@H]2CCCC[C@H]2N1 DWAFYCQODLXJNR-BNTLRKBRSA-L 0.000 description 1
- 229960001756 oxaliplatin Drugs 0.000 description 1
- GSEZHCLWHDZJAB-UHFFFAOYSA-N oxan-4-yl methanesulfonate Chemical compound CS(=O)(=O)OC1CCOCC1 GSEZHCLWHDZJAB-UHFFFAOYSA-N 0.000 description 1
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 125000004095 oxindolyl group Chemical group N1(C(CC2=CC=CC=C12)=O)* 0.000 description 1
- 150000002924 oxiranes Chemical class 0.000 description 1
- 229960001592 paclitaxel Drugs 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000004963 pathophysiological condition Effects 0.000 description 1
- 229960005079 pemetrexed Drugs 0.000 description 1
- WBXPDJSOTKVWSJ-ZDUSSCGKSA-N pemetrexed Chemical compound C=1NC=2NC(N)=NC(=O)C=2C=1CCC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 WBXPDJSOTKVWSJ-ZDUSSCGKSA-N 0.000 description 1
- 235000019371 penicillin G benzathine Nutrition 0.000 description 1
- 229960002340 pentostatin Drugs 0.000 description 1
- FPVKHBSQESCIEP-JQCXWYLXSA-N pentostatin Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(N=CNC[C@H]2O)=C2N=C1 FPVKHBSQESCIEP-JQCXWYLXSA-N 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- JRKICGRDRMAZLK-UHFFFAOYSA-L persulfate group Chemical group S(=O)(=O)([O-])OOS(=O)(=O)[O-] JRKICGRDRMAZLK-UHFFFAOYSA-L 0.000 description 1
- 230000004526 pharmaceutical effect Effects 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- PARWUHTVGZSQPD-UHFFFAOYSA-N phenylsilane Chemical compound [SiH3]C1=CC=CC=C1 PARWUHTVGZSQPD-UHFFFAOYSA-N 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 1
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-N picric acid Chemical class OC1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-N 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000005936 piperidyl group Chemical group 0.000 description 1
- 125000005547 pivalate group Chemical group 0.000 description 1
- 150000003057 platinum Chemical class 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- OKBMCNHOEMXPTM-UHFFFAOYSA-M potassium peroxymonosulfate Chemical compound [K+].OOS([O-])(=O)=O OKBMCNHOEMXPTM-UHFFFAOYSA-M 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000012041 precatalyst Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 229960005205 prednisolone Drugs 0.000 description 1
- OIGNJSKKLXVSLS-VWUMJDOOSA-N prednisolone Chemical compound O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OIGNJSKKLXVSLS-VWUMJDOOSA-N 0.000 description 1
- 229960004618 prednisone Drugs 0.000 description 1
- XOFYZVNMUHMLCC-ZPOLXVRWSA-N prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 description 1
- 238000002953 preparative HPLC Methods 0.000 description 1
- 238000003825 pressing Methods 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 229960000624 procarbazine Drugs 0.000 description 1
- CPTBDICYNRMXFX-UHFFFAOYSA-N procarbazine Chemical compound CNNCC1=CC=C(C(=O)NC(C)C)C=C1 CPTBDICYNRMXFX-UHFFFAOYSA-N 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 239000000583 progesterone congener Substances 0.000 description 1
- 229960002429 proline Drugs 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 230000004224 protection Effects 0.000 description 1
- 239000012264 purified product Substances 0.000 description 1
- 239000000649 purine antagonist Substances 0.000 description 1
- 239000002212 purine nucleoside Substances 0.000 description 1
- 239000003790 pyrimidine antagonist Substances 0.000 description 1
- 125000006085 pyrrolopyridyl group Chemical group 0.000 description 1
- CZAAKPFIWJXPQT-UHFFFAOYSA-N quinazolin-2-amine Chemical class C1=CC=CC2=NC(N)=NC=C21 CZAAKPFIWJXPQT-UHFFFAOYSA-N 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 230000008707 rearrangement Effects 0.000 description 1
- 108091006082 receptor inhibitors Proteins 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 150000003873 salicylate salts Chemical class 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 238000009097 single-agent therapy Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 201000000498 stomach carcinoma Diseases 0.000 description 1
- 229960001052 streptozocin Drugs 0.000 description 1
- ZSJLQEPLLKMAKR-GKHCUFPYSA-N streptozocin Chemical compound O=NN(C)C(=O)N[C@H]1[C@@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O ZSJLQEPLLKMAKR-GKHCUFPYSA-N 0.000 description 1
- 150000003890 succinate salts Chemical class 0.000 description 1
- 150000003871 sulfonates Chemical class 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 208000034223 susceptibility to 2 systemic lupus erythematosus Diseases 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 229960001603 tamoxifen Drugs 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 238000003419 tautomerization reaction Methods 0.000 description 1
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
- 229940066453 tecentriq Drugs 0.000 description 1
- NRUKOCRGYNPUPR-QBPJDGROSA-N teniposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@@H](OC[C@H]4O3)C=3SC=CC=3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 NRUKOCRGYNPUPR-QBPJDGROSA-N 0.000 description 1
- 229960001278 teniposide Drugs 0.000 description 1
- JJXOIFHXNBFRNV-UHFFFAOYSA-N tert-butyl (2-methylpropan-2-yl)oxycarbonyl carbonate Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C.CC(C)(C)OC(=O)OC(=O)OC(C)(C)C JJXOIFHXNBFRNV-UHFFFAOYSA-N 0.000 description 1
- QKSQWQOAUQFORH-VAWYXSNFSA-N tert-butyl (ne)-n-[(2-methylpropan-2-yl)oxycarbonylimino]carbamate Chemical compound CC(C)(C)OC(=O)\N=N\C(=O)OC(C)(C)C QKSQWQOAUQFORH-VAWYXSNFSA-N 0.000 description 1
- KTMLKFVRVCCJCU-UHFFFAOYSA-N tert-butyl 1-(hydrazinecarbonyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CC2CC21C(=O)NN KTMLKFVRVCCJCU-UHFFFAOYSA-N 0.000 description 1
- WZRJRJLKPLISJM-UHFFFAOYSA-N tert-butyl 3-(hydrazinecarbonyl)azepane-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCCCC(C(=O)NN)C1 WZRJRJLKPLISJM-UHFFFAOYSA-N 0.000 description 1
- 208000024662 testicular seminoma Diseases 0.000 description 1
- 210000001550 testis Anatomy 0.000 description 1
- 229960003604 testosterone Drugs 0.000 description 1
- 229960001712 testosterone propionate Drugs 0.000 description 1
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 1
- XXSLZJZUSYNITM-UHFFFAOYSA-N tetrabutylammonium tribromide Chemical compound Br[Br-]Br.CCCC[N+](CCCC)(CCCC)CCCC XXSLZJZUSYNITM-UHFFFAOYSA-N 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000003507 tetrahydrothiofenyl group Chemical group 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- 230000004797 therapeutic response Effects 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 125000004588 thienopyridyl group Chemical group S1C(=CC2=C1C=CC=N2)* 0.000 description 1
- 150000003567 thiocyanates Chemical class 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 229960001196 thiotepa Drugs 0.000 description 1
- 201000002510 thyroid cancer Diseases 0.000 description 1
- 210000001685 thyroid gland Anatomy 0.000 description 1
- 229960003087 tioguanine Drugs 0.000 description 1
- 238000003354 tissue distribution assay Methods 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-M toluenesulfonate group Chemical group C=1(C(=CC=CC1)S(=O)(=O)[O-])C LBLYYCQCTBFVLH-UHFFFAOYSA-M 0.000 description 1
- 125000005490 tosylate group Chemical group 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 230000001960 triggered effect Effects 0.000 description 1
- NOYPYLRCIDNJJB-UHFFFAOYSA-N trimetrexate Chemical compound COC1=C(OC)C(OC)=CC(NCC=2C(=C3C(N)=NC(N)=NC3=CC=2)C)=C1 NOYPYLRCIDNJJB-UHFFFAOYSA-N 0.000 description 1
- 229960001099 trimetrexate Drugs 0.000 description 1
- 229910000404 tripotassium phosphate Inorganic materials 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 201000008827 tuberculosis Diseases 0.000 description 1
- 210000003171 tumor-infiltrating lymphocyte Anatomy 0.000 description 1
- 231100000588 tumorigenic Toxicity 0.000 description 1
- 230000000381 tumorigenic effect Effects 0.000 description 1
- 230000005951 type IV hypersensitivity Effects 0.000 description 1
- 208000027930 type IV hypersensitivity disease Diseases 0.000 description 1
- ZDPHROOEEOARMN-UHFFFAOYSA-N undecanoic acid Chemical class CCCCCCCCCCC(O)=O ZDPHROOEEOARMN-UHFFFAOYSA-N 0.000 description 1
- 230000003827 upregulation Effects 0.000 description 1
- 229960001055 uracil mustard Drugs 0.000 description 1
- 210000003932 urinary bladder Anatomy 0.000 description 1
- VBEQCZHXXJYVRD-GACYYNSASA-N uroanthelone Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CS)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)C(C)C)[C@@H](C)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCSC)NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)CNC(=O)CNC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CS)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CS)NC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O)C(C)C)[C@@H](C)CC)C1=CC=C(O)C=C1 VBEQCZHXXJYVRD-GACYYNSASA-N 0.000 description 1
- 229960003048 vinblastine Drugs 0.000 description 1
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 description 1
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 1
- 229960004528 vincristine Drugs 0.000 description 1
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 1
- 229960004854 viral vaccine Drugs 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 239000004034 viscosity adjusting agent Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
- GTLDTDOJJJZVBW-UHFFFAOYSA-N zinc cyanide Chemical compound [Zn+2].N#[C-].N#[C-] GTLDTDOJJJZVBW-UHFFFAOYSA-N 0.000 description 1
- 150000003952 β-lactams Chemical class 0.000 description 1
- 150000003953 γ-lactams Chemical class 0.000 description 1
- 150000003954 δ-lactams Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
- C07K16/2818—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against CD28 or CD152
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Definitions
- the present invention relates to novel compounds that inhibit at least one of the A2a and A2b adenosine receptors, and pharmaceutically acceptable salts thereof, and compositions comprising such compound(s) and salts, methods for the synthesis of such compounds, and their use in the treatment of a variety of diseases, conditions, or disorders that are mediated, at least in part, by the adenosine A2a receptor and/or the adenosine A2b receptor.
- diseases, conditions, and disorders include but are not limited to cancer and immune-related disorders.
- the invention further relates to combination therapies, including but not limited to a combination comprising a compound of the invention and a PD-1 antagonist.
- Adenosine is a purine nucleoside compound comprised of adenine and ribofuranose, a ribose sugar molecule.
- Adenosine occurs naturally in mammals and plays important roles in various biochemical processes, including energy transfer (as adenosine triphosphate and adenosine monophosphate) and signal transduction (as cyclic adenosine monophosphate).
- Adenosine also plays a causative role in processes associated with vasodilation, including cardiac vasodilation. It also acts as a neuromodulator (e.g., it is thought to be involved in promoting sleep). In addition to its involvement in these biochemical processes, adenosine is used as a therapeutic antiarrhythmic agent to treat supraventricular tachycardia and other indications.
- the adenosine receptors are a class of purinergic G protein-coupled receptors with adenosine as the endogenous ligand.
- the four types of adenosine receptors in humans are referred to as A1, A2a, A2b, and A3.
- Modulation of A1 has been proposed for the management and treatment of neurological disorders, asthma, and heart and renal failure, among others.
- Modulation of A3 has been proposed for the management and treatment of asthma and chronic obstructive pulmonary diseases, glaucoma, cancer, stroke, and other indications. Modulation of the A2a and A2b receptors are also believed to be of potential therapeutic use.
- A2a antagonists are believed to exhibit antidepressant properties and to stimulate cognitive functions.
- A2a receptors are present in high density in the basal ganglia, known to be important in the control of movement.
- A2a receptor antagonists are believed to be useful in the treatment of depression and to improve motor impairment due to neurodegenerative diseases such as Parkinson's disease, senile dementia (as in Alzheimer's disease), and in various psychoses of organic origin.
- A2a receptors and A2b receptors expressed on a variety of immune cells and endothelial cells, has been established as having an important role in protecting tissues during inflammatory responses. In this way (and others), tumors have been shown to evade host responses by inhibiting immune function and promoting tolerance. (See, e.g., Fishman, P., et al., Handb. Exp. Pharmacol. (2009) 193:399-441). Moreover, A2a and A2b cell surface adenosine receptors have been found to be upregulated in various tumor cells.
- antagonists of the A2a and/or A2b adenosine receptors represent a new class of promising oncology therapeutics.
- activation of A2a adenosine receptors results in the inhibition of the immune response to tumors by a variety of cell types, including but not limited to: the inhibition of natural killer cell cytotoxicity, the inhibition of tumor-specific CD4+/CD8+ activity, promoting the generation of LAG-3 and Foxp3+ regulatory T-cells, and mediating the inhibition of regulatory T-cells.
- Adenosine A2a receptor inhibition has also been shown to increase the efficacy of PD-1 inhibitors through enhanced anti-tumor T cell responses.
- a cancer immunotherapeutic regimen that includes an antagonist of the A2a and/or A2b receptors, alone or together with one or more other therapeutic agents designed to mitigate immune suppression, may result in enhanced tumor immunotherapy.
- Cancer cells release ATP into the tumor microenvironment when treated with chemotherapy and radiation therapy, which is subsequently converted to adenosine.
- the adenosine can then bind to A2a receptors and blunt the anti-tumor immune response through mechanisms such as those described above.
- the administration of A2a receptor antagonists during chemotherapy or radiation therapy has been proposed to lead to the expansion of the tumor-specific T-cells while simultaneously preventing the induction of tumor-specific regulatory T-cells. (Young, A., et al., Cancer Discovery (2014) 4:879-888).
- A2a receptor antagonists may be useful in combination with checkpoint blockers.
- the combination of a PD-1 inhibitor and an adenosine A2a receptor inhibitor is thought to mitigate the ability of tumors to inhibit the activity of tumor-specific effector T-cells.
- the A2b receptor is a G protein-coupled receptor found in various cell types. A2b receptors require higher concentrations of adenosine for activation than the other adenosine receptor subtypes, including A2a. (Fredholm, B B., et al., Biochem. Pharmacol. (2001) 61:443-448). Conditions which activate A2b have been seen, for example, in tumors where hypoxia is observed. The A2b receptor may thus play an important role in pathophysiological conditions associated with massive adenosine release.
- A2b receptor-mediated inhibition While the pathway(s) associated with A2b receptor-mediated inhibition are not well understood, it is believed that the inhibition of A2b receptors (alone or together with A2a receptors) may block pro-tumorigenic functions of adenosine in the tumor microenvironment, including suppression of T-cell function and angiogenesis, and thus expand the types of cancers treatable by the inhibition of these receptors.
- A2b receptors are expressed primarily on myeloid cells.
- the engagement of A2b receptors on myeloid derived suppressor cells (MDSCs) results in their expansion in vitro (Ryzhov, S. et al., J. Immunol. 2011, 187:6120-6129).
- MDSCs suppress T-cell proliferation and anti-tumor immune responses.
- Selective inhibitors of A2b receptors and A2b receptor knockouts have been shown to inhibit tumor growth in mouse models by increasing MDSCs in the tumor microenvironment (Iannone, R., et al., Neoplasia Vol. 13 No. 12, (2013) pp. 1400-1409; Ryzhov, S., et al., Neoplasia (2008) 10: 987-995).
- A2b receptor inhibition has become an attractive biological target for the treatment of a variety of cancers involving myeloid cells.
- cancers that express A2b receptors can be readily obtained through analysis of the publicly available TCGA database.
- Such cancers include lung, colorectal, head and neck, and cervical cancer, among others, and are discussed in further detail below.
- Angiogenesis plays an important role in tumor growth.
- the angiogenesis process is highly regulated by a variety of factors and is triggered by adenosine under particular circumstances that are associated with hypoxia.
- the A2b receptor is expressed in human microvascular endothelial cells, where it plays an important role in the regulation of the expression of angiogenic factors such as the vascular endothelial growth factor (VEGF).
- VEGF vascular endothelial growth factor
- hypoxia has been observed to cause an upregulation of the A2b receptors, suggesting that inhibition of A2b receptors may limit tumor growth by limiting the oxygen supply to the tumor cells.
- the present invention provides compounds (hereinafter referred to as compounds of the invention) which, surprisingly and advantageously, have been found to be inhibitors of the adenosine A2a receptor and/or the adenosine A2b receptor.
- the compounds of the invention have a structure in accordance with the structural Formula (I):
- compositions comprising at least one compound of the invention, or a pharmaceutically acceptable salt thereof, in a pharmaceutically acceptable carrier or diluent.
- Such compositions according to the invention may optionally further include one or more additional therapeutic agents as described herein.
- the present invention provides a method for treating or preventing a disease, condition, or disorder that is mediated, at least in part, by the adenosine A2a receptor and/or the adenosine A2b receptor in a subject (e.g., an animal or human) in need thereof, said method comprising administering to the subject a therapeutically effective amount of at least one compound of the invention, or a pharmaceutically acceptable salt thereof, alone or in combination with one or more additional therapeutic agents.
- any variable not explicitly defined in the embodiment is as defined in Formula (I). In each of the embodiments described herein, each variable is selected independently of the other unless otherwise noted.
- the compounds of the invention have the structural Formula (I):
- R 1 is selected from F, Cl, (C 1 -C 6 )alkyl, and O(C 1 -C 6 )alkyl;
- R 2 is selected from H, F, Cl, (C 1 -C 6 )alkyl, and O(C 1 -C 6 )alkyl;
- ring A is a moiety selected from:
- R 3 is selected from pyrazolyl, triazolyl, and pyridinyl, wherein said pyrazolyl and said triazolyl, are substituted with 1 or 2 R 3A groups, and wherein said pyridinyl is substituted with 1, 2, or 3 R 3A groups, wherein:
- each R 3A is independently selected from (C 1 -C 6 )alkyl, O(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl-OH, (C 1 -C 6 )haloalkyl, O(C 1 -C 6 )haloalkyl, oxo, (C 1 -C 4 )alkylC(O)(C 1 -C 3 )alkyl, (C 1 -C 4 )alkylCH(OH)(C 1 -C 3 )alkyl, (C 1 -C 4 )alkylS(O) 2 (C 1 -C 3 )alkyl, —(CH 2 ) n (C 3 -C 7 )cycloalkyl, and —(CH 2 ) n 4-7 membered monocyclic heterocycloalkyl comprising 1 or 2 ring heteroatoms selected from oxygen and nitrogen, wherein said (C 3 -C 7 )cycloalky
- n 0, 1, or 2;
- R A1 is selected from H, and (C 1 -C 4 )alkyl
- R A2 is selected from H, F, and (C 1 -C 4 )alkyl
- R A3 is selected from H, F, and (C 1 -C 4 )alkyl
- R A4 is selected from H and OH
- R A5 is selected from H, F, and (C 1 -C 4 )alkyl.
- the compounds of the invention have the structural Formula (I.1):
- the compounds of the invention have the structural Formula (I.2):
- R 1 is selected from F, Cl, and OCH 3 ;
- R 2 is selected from H, F, Cl, CH 3 , and OCH 3 .
- R 1 is F
- R 2 is selected from H, F, Cl, CH 3 , and OCH 3 .
- R 1 is Cl
- R 2 is selected from H, F, Cl, CH 3 , and OCH 3 .
- R 1 is F
- R 2 is OCH 3 .
- R 1 is F
- R 2 is F.
- R 1 is F
- R 2 is H.
- ring A is a moiety selected from:
- R 3 , R A1 , R A2 , R A3 , and R A5 are as defined in Formula (I); and wherein R 1 and R 2 are as defined in Formula (I) or as defined in any of the alternative embodiments of R 1 and R 2 described above.
- ring A is a moiety selected from:
- R 3 is selected from
- each R 3A is as defined in Formula (I);
- each R Aa is independently selected from (C 1 -C 4 )alkyl, O(C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl, and O(C 1 -C 4 )haloalkyl;
- R A1 , R A2 , R A3 , and R A5 are as defined in Formula (I);
- R 1 and R 2 are as defined in Formula (I) or as defined in any of the alternative embodiments of R 1 and R 2 described above.
- ring A is a moiety selected from:
- R 3 is selected from
- each R 3Aa is independently selected from (C 1 -C 4 )alkyl, O(C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl, and O(C 1 -C 4 )haloalkyl;
- R A1 , R A2 , R A3 , and R A5 are as defined in Formula (I);
- R 1 and R 2 are as defined in Formula (I) or as defined in any of the alternative embodiments of R 1 and R 2 described above.
- R A1 is selected from H, CH 3 , and CH 2 CH 3 ;
- R A2 is selected from H, F, CH 3 , and CH 2 CH 3 ;
- R A3 is selected from H and F;
- R A5 is H.
- R A1 is selected from H and CH 3 ;
- R A2 is H
- R A3 is H
- R A5 is H.
- R A1 is H
- R A2 is H
- R A3 is H
- R A5 is H.
- ring A is the moiety:
- R 3 and R A3 are as defined in Formula (I); and wherein R 1 and R 2 are as defined in Formula (I) or as defined in any of the alternative embodiments of R 1 and R 2 described above.
- ring A is the moiety:
- R 3 is selected from
- R A3 is as defined in Formula (I).
- R 1 and R 2 are as defined in Formula (I) or as defined in any of the alternative embodiments of R 1 and R 2 described above.
- ring A is the moiety:
- R 3 is selected from
- each R 3A is a moiety selected from:
- each R 3Aa is independently selected from (C 1 -C 4 )alkyl, O(C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl, and O(C 1 -C 4 )haloalkyl;
- R A3 is as defined in Formula (I).
- R 1 and R 2 are as defined in Formula (I) or as defined in any of the alternative embodiments of R 1 and R 2 described above.
- R A3 is selected from H and F.
- R A3 is H.
- ring A is the moiety:
- R 3 is as defined in Formula (I); and wherein R 1 and R 2 are as defined in Formula (I) or as defined in any of the alternative embodiments of R 1 and R 2 described above.
- ring A is the moiety:
- R 3 is selected from
- each R 3A is as defined in Formula (I);
- each R 3Aa is independently selected from (C 1 -C 4 )alkyl, O(C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl, and O(C 1 -C 4 )haloalkyl;
- R 1 and R 2 are as defined in Formula (I) or as defined in any of the alternative embodiments of R 1 and R 2 described above.
- ring A is the moiety:
- R 3 is selected from
- each R 3A is a moiety selected from:
- each R 3Aa is independently selected from (C 1 -C 4 )alkyl, O(C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl, and O(C 1 -C 4 )haloalkyl;
- R 1 and R 2 are as defined in Formula (I) or as defined in any of the alternative embodiments of R 1 and R 2 described above.
- ring A is the moiety:
- R 3 is as defined in Formula (I); and wherein R 1 and R 2 are as defined in Formula (I) or as defined in any of the alternative embodiments of R 1 and R 2 described above.
- ring A is the moiety:
- R 3 is selected from
- each R 3A is as defined in Formula (I);
- each R 3Aa is independently selected from (C 1 -C 4 )alkyl, O(C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl, and O(C 1 -C 4 )haloalkyl;
- R 1 and R 2 are as defined in Formula (I) or as defined in any of the alternative embodiments of R 1 and R 2 described above.
- ring A is the moiety:
- R 3 is selected from
- each R 3A is a moiety selected from:
- each R 3Aa is independently selected from (C 1 -C 4 )alkyl, O(C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl, and O(C 1 -C 4 )haloalkyl;
- R 1 and R 2 are as defined in Formula (I) or as defined in any of the alternative embodiments of R 1 and R 2 described above.
- ring A is the moiety:
- R 3 , R A1 , R A2 , and R A3 are as defined in Formula (I); and wherein R 1 and R 2 are as defined in Formula (I) or as defined in any of the alternative embodiments of R 1 and R 2 described above.
- ring A is the moiety:
- R 3 is selected from
- each R 3A is as defined in Formula (I);
- each R 3Aa is independently selected from (C 1 -C 4 )alkyl, O(C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl, and O(C 1 -C 4 )haloalkyl;
- R A1 , R A2 , and R A3 are as defined in Formula (I);
- R 1 and R 2 are as defined in Formula (I) or as defined in any of the alternative embodiments of R 1 and R 2 described above.
- ring A is the moiety:
- R 3 is selected from
- each R 3A is a moiety selected from:
- each R 3Aa is independently selected from (C 1 -C 4 )alkyl, O(C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl, and O(C 1 -C 4 )haloalkyl;
- R A1 , R A2 , and R A3 are as defined in Formula (I);
- R 1 and R 2 are as defined in Formula (I) or as defined in any of the alternative embodiments of R 1 and R 2 described above.
- R A1 is selected from H, CH 3 , and CH 2 CH 3 ;
- R A2 is selected from H, F, CH 3 , and CH 2 CH 3 ;
- R A3 is selected from H and F.
- R A1 is selected from H and CH 3 ;
- R A2 is H
- R A3 is H.
- R A1 is H
- R A2 is H
- R A3 is H.
- ring A is the moiety:
- R 3 , R A1 , R A2 , and R A3 are as defined in Formula (I);
- R 1 and R 2 are as defined in Formula (I) or as defined in any of the alternative embodiments of R 1 and R 2 described above.
- ring A is the moiety:
- R 3 is selected from
- R A1 , R A2 , and R A3 are as defined in Formula (I);
- R 1 and R 2 are as defined in Formula (I) or as defined in any of the alternative embodiments of R 1 and R 2 described above.
- ring A is the moiety:
- R 3 is selected from
- each R 3A is a moiety selected from:
- each R 3Aa is independently selected from (C 1 -C 4 )alkyl, O(C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl, and O(C 1 -C 4 )haloalkyl;
- R A1 , R A2 , and R A3 are as defined in Formula (I);
- R 1 and R 2 are as defined in Formula (I) or as defined in any of the alternative embodiments of R 1 and R 2 described above.
- R A1 is selected from H, CH 3 , and CH 2 CH 3 ;
- R A2 is selected from H, F, CH 3 , and CH 2 CH 3 ;
- R A3 is selected from H and F.
- R A1 is selected from H and CH 3 ;
- R A2 is H
- R A3 is H.
- R A1 is H
- R A2 is H
- R A3 is H.
- ring A is the moiety:
- R 3 , R A1 , R A2 , R A3 and R A4 are as defined in Formula (I);
- R 1 and R 2 are as defined in Formula (I) or as defined in any of the alternative embodiments of R 1 and R 2 described above.
- ring A is the moiety:
- R 3 is selected from
- each R 3A is as defined in Formula (I);
- each R 3Aa is independently selected from (C 1 -C 4 )alkyl, O(C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl, and O(C 1 -C 4 )halo alkyl;
- R A1 , R A2 , R A3 and R A4 re as defined in Formula (I);
- R 1 and R 2 are as defined in Formula (I) or as defined in any of the alternative embodiments of R 1 and R 2 described above.
- ring A is the moiety:
- R 3 is selected from
- each R 3A is a moiety selected from:
- each R Aa is independently selected from (C 1 -C 4 )alkyl, O(C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl, and O(C 1 -C 4 )haloalkyl;
- R A1 ; R A2 ; R A3 and R A4 re as defined in Formula (I);
- R 1 and R 2 are as defined in Formula (I) or as defined in any of the alternative embodiments of R 1 and R 2 described above.
- R A1 is selected from H, CH 3 , and CH 2 CH 3 ;
- R A2 is selected from H, F, CH 3 , and CH 2 CH 3 ;
- R A3 is selected from H and F;
- R A4 is selected from H and OH.
- R A1 is H
- R A2 is H
- R A3 is H
- R A4 is selected from H and OH.
- the compounds of the invention comprise those compounds identified herein as examples in the tables below, and pharmaceutically acceptable salts thereof.
- compositions comprising a pharmaceutically acceptable carrier and a compound of the invention or a pharmaceutically acceptable salt thereof.
- Such compositions according to the invention may optionally further include one or more additional therapeutic agents as described herein.
- the present invention provides a method for the manufacture of a medicament or a composition which may be useful for treating diseases, conditions, or disorders that are mediated, at least in part, by the adenosine A2a receptor and/or the adenosine A2b receptor, comprising combining a compound of the invention with one or more pharmaceutically acceptable carriers.
- the present invention provides a method for treating or preventing a disease, condition, or disorder that is mediated, at least in part, by the adenosine A2a receptor and/or the adenosine A2b receptor in a subject (e.g., an animal or human) in need thereof, said method comprising administering to the subject in need thereof a therapeutically effective amount of at least one compound of the invention, or a pharmaceutically acceptable salt thereof, alone or in combination with one or more additional therapeutic agents.
- a subject e.g., an animal or human
- the disease, condition or disorder is a cancer.
- Any cancer for which a PD-1 antagonist and/or an A2a and/or A2b inhibitor are thought to be useful by those of ordinary skill in the art are contemplated as cancers treatable by this embodiment, either as a monotherapy or in combination with other therapeutic agents discussed below.
- Cancers that express high levels of A2a receptors or A2b receptors are among those cancers contemplated as treatable by the compounds of the invention. Examples of cancers that express high levels of A2a and/or A2b receptors may be discerned by those of ordinary skill in the art by reference to the Cancer Genome Atlas (TCGA) database.
- TCGA Cancer Genome Atlas
- Non-limiting examples of cancers that express high levels of A2a receptors include cancers of the kidney, breast, lung, and liver.
- Non-limiting examples of cancers that express high levels of the A2b receptor include lung, colorectal, head & neck cancer, and cervical cancer.
- one embodiment provides a method of treating cancer comprising administering an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, to a subject in need of such treatment, wherein said cancer is a cancer that expresses a high level of A2a receptor.
- a related embodiment provides a method of treating cancer comprising administering an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, to a subject in need of such treatment, wherein said cancer is selected from kidney (or renal) cancer, breast cancer, lung cancer, and liver cancer.
- Another embodiment provides a method of treating cancer comprising administering an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, to a subject in need of such treatment, wherein said cancer is a cancer that expresses a high level of A2b receptor.
- a related embodiment provides a method of treating cancer comprising administering an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, to a subject in need of such treatment, wherein said cancer is selected from lung cancer, colorectal cancer, head & neck cancer, and cervical cancer.
- cancers which may be treatable by administration of a compound of the invention (alone or in combination with one or more additional agents described below) include cancers of the prostate (including but not limited to metastatic castration resistant prostate cancer), colon, rectum, pancreas, cervix, stomach, endometrium, brain, liver, bladder, ovary, testis, head, neck, skin (including melanoma and basal carcinoma), mesothelial lining, white blood cell (including lymphoma and leukemia) esophagus, breast, muscle, connective tissue, lung (including but not limited to small cell lung cancer, non-small cell lung cancer, and lung adenocarcinoma), adrenal gland, thyroid, kidney, or bone.
- prostate including but not limited to metastatic castration resistant prostate cancer
- colon including rectum, pancreas, cervix, stomach, endometrium, brain, liver, bladder, ovary, testis, head, neck, skin (including melanoma and basal carcinoma), mes
- Additional cancers treatable by a compound of the invention include glioblastoma, mesothelioma, renal cell carcinoma, gastric carcinoma, sarcoma, choriocarcinoma, cutaneous basocellular carcinoma, and testicular seminoma, and Kaposi's sarcoma.
- the disease, condition or disorder is a central nervous system or a neurological disorder.
- diseases, conditions or disorders include movement disorders such as tremors, bradykinesias, gait disorders, dystonias, dyskinesias, tardive dyskinesias, other extrapyramidal syndromes, Parkinson's disease, and disorders associated with Parkinson's disease.
- the compounds of the invention also have the potential, or are believed to have the potential, for use in preventing or reducing the effect of drugs that cause or worsen such movement disorders.
- the disease, condition or disorder is an infective disorder.
- diseases, conditions or disorders include an acute or chronic viral infection, a bacterial infection, a fungal infection, or a parasitic infection.
- the viral infection is human immunodeficiency virus.
- the viral infection is cytomegalovirus.
- the disease, condition or disorder is an immune-related disease, condition or disorder.
- immune-related diseases, conditions, or disorders include multiple sclerosis and bacterial infections. (See, e.g., Safarzadeh, E. et al., Inflamm Res 2016 65(7):511-20; and Antonioli, L., et al., Immunol Lett S0165-2478(18)30172-X 2018).
- diseases, conditions, and disorders that have the potential to be treated or prevented, in whole or in part, by the inhibition of the A2a and/or A2b adenosine receptor(s) are also candidate indications for the compounds of the invention and salts thereof.
- Non-limiting examples of other diseases, conditions or disorders in which a compound of the invention, or a pharmaceutically acceptable salt thereof, may be useful include the treatment of hypersensitivity reaction to a tumor antigen and the amelioration of one or more complications related to bone marrow transplant or to a peripheral blood stem cell transplant.
- the present invention provides a method for treating a subject receiving a bone marrow transplant or a peripheral blood stem cell transplant by administering to said subject a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, sufficient to increase the delayed-type hypersensitivity reaction to tumor antigen, to delay the time-to-relapse of post-transplant malignancy, to increase relapse-free survival time post-transplant, and/or to increase long-term post-transplant survival.
- the present invention provides methods for the use of a compound of the invention, or a pharmaceutically acceptable salt thereof, (or a pharmaceutically acceptable composition comprising a compound of the invention or pharmaceutically acceptable salt thereof) in combination with one or more additional agents.
- additional agents may have some adenosine A2a and/or A2b receptor activity, or, alternatively, they may function through distinct mechanisms of action.
- the compounds of the invention may be used in combination with one or more other drugs in the treatment, prevention, suppression or amelioration of diseases or conditions for which the compounds of the invention or the other drugs described herein may have utility, where the combination of the drugs together are safer or more effective than either drug alone.
- the combination therapy may have an additive or synergistic effect.
- Such other drug(s) may be administered in an amount commonly used therefore, contemporaneously or sequentially with a compound of the invention or a pharmaceutically acceptable salt thereof.
- the pharmaceutical composition may in specific embodiments contain such other drugs and the compound of the invention or its pharmaceutically acceptable salt in separate doses or in unit dosage form.
- the combination therapy may also include therapies in which the compound of the invention or its pharmaceutically acceptable salt and one or more other drugs are administered sequentially, on different or overlapping schedules.
- the compounds of the invention and the other active ingredients may be used in lower doses than when each is used singly.
- the pharmaceutical compositions comprising the compounds of the invention include those that contain one or more other active ingredients, in addition to a compound of the invention or a pharmaceutically acceptable salt thereof.
- the weight ratio of the compound of the present invention to the second active ingredient may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used. Thus, for example, when a compound of the invention is used in combination with another agent, the weight ratio of the compound of the present invention to the other agent may generally range from about 1000:1 to about 1:1000, in particular embodiments from about 200:1 to about 1:200. Combinations of a compound of the present invention and other active ingredients will generally also be within the aforementioned range, but in each case, an effective dose of each active ingredient should generally be used.
- the administration of an A2a receptor antagonist, an A2b receptor antagonist, and/or an A2a/A2b receptor dual antagonist according to the invention may enhance the efficacy of immunotherapies such as PD-1 antagonists.
- the additional therapeutic agent comprises an anti-PD-1 antibody.
- the additional therapeutic agent is an anti-PD-L1 antibody.
- PD-1 is recognized as having an important role in immune regulation and the maintenance of peripheral tolerance.
- PD-1 is moderately expressed on naive T-cells, B-cells and NKT-cells and up-regulated by T-cell and B-cell receptor signaling on lymphocytes, monocytes and myeloid cells (Sharpe et al., Nature Immunology (2007); 8:239-245).
- PD-1, PD-L1 (B7-H1) and PD-L2 (B7-DC) are expressed in human cancers arising in various tissues.
- PD-L1 expression correlated with poor prognosis and reduced overall survival irrespective of subsequent treatment.
- Nat Med. 8(8):793-800 (2002); Yang et al., Invest Ophthamol Vis Sci. 49: 2518-2525 (2008); Ghebeh et al., Neoplasia 8:190-198 (2006); Hamanishi et al., Proc.
- PD-1 expression on tumor infiltrating lymphocytes was found to mark dysfunctional T-cells in breast cancer and melanoma (Ghebeh et al., BMC Cancer. 2008 8:5714-15 (2008); and Ahmadzadeh et al., Blood 114: 1537-1544 (2009)) and to correlate with poor prognosis in renal cancer (Thompson et al., Clinical Cancer Research 15: 1757-1761(2007)).
- PD-L1 expressing tumor cells interact with PD-1 expressing T-cells to attenuate T-cell activation and to evade immune surveillance, thereby contributing to an impaired immune response against the tumor.
- Immune checkpoint therapies targeting the PD-1 axis have resulted in technological improvements in clinical response in multiple human cancers (Brahmer, et al., N Engl J Med 2012, 366: 2455-65; Garon et al., N Engl J Med 2015, 372: 2018-28; Hamid et al., N Engl J Med 2013, 369: 134-44; Robert et al., Lancet 2014, 384: 1109-17; Robert et al., N Engl J Med 2015, 372: 2521-32; Robert et al., N Engl J Med 2015, 372: 320-30; Topalian et al., N Engl J Med 2012, 366: 2443-54; Topalian et al., J Clin Oncol 2014, 32: 1020-30; and Wolchok et al., N Engl J Med 2013, 369: 122-33).
- PD-1 antagonist means any chemical compound or biological molecule that blocks binding of PD-L1 expressed on a cancer cell to PD-1 expressed on an immune cell (T-cell, B-cell or NKT cell) and preferably also blocks binding of PD-L2 expressed on a cancer cell to the immune-cell expressed PD-1.
- Alternative names or synonyms for PD-1 and its ligands include: PDCD1, PD1, CD279 and SLEB2 for PD-1; PDCD1L1, PDL1, B7H1, B7-4, CD274 and B7-H for PD-L1; and PDCD1L2, PDL2, B7-DC, Btdc and CD273 for PD-L2.
- the PD-1 antagonist blocks binding of human PD-L1 to human PD-1, and preferably blocks binding of both human PD-L1 and PD-L2 to human PD-1.
- Human PD-1 amino acid sequences can be found in NCBI Locus No.: NP 005009.
- Human PD-L1 and PD-L2 amino acid sequences can be found in NCBI Locus No.: NP_054862 and NP_079515, respectively.
- PD-1 antagonists useful in any of the treatment methods, medicaments and uses of the present invention include a monoclonal antibody (mAb), or antigen binding fragment thereof, which specifically binds to PD-1 or PD-L1, and preferably specifically binds to human PD-1 or human PD-L1.
- the mAb may be a human antibody, a humanized antibody or a chimeric antibody, and may include a human constant region.
- the human constant region is selected from the group consisting of IgG1, IgG2, IgG3 and IgG4 constant regions, and in preferred embodiments, the human constant region is an IgG1 or IgG4 constant region.
- the antigen binding fragment is selected from the group consisting of Fab, Fab′-SH, F(ab′)2, scFv and Fv fragments.
- PD-1 antagonists include, but are not limited to, pembrolizumab (KEYTRUDA®, Merck and Co., Inc., Kenilworth, N.J., USA).
- pembrolizumab (formerly known as MK-3475, SCH 900475 and lambrolizumab and sometimes referred to as “pembro”) is a humanized IgG4 mAb with the structure described in WHO Drug Information, Vol. 27, No. 2, pages 161-162 (2013).
- PD-1 antagonists include nivolumab (OPDIVO®, Bristol-Myers Squibb Company, Princeton, N.J., USA), atezolizumab (MPDL3280A; TECENTRIQ®, Genentech, San Francisco, Calif., USA), durvalumab (IMFINZI®, Astra Zeneca Pharmaceuticals, LP, Wilmington, Del., and avelumab (BAVENCIO®, Merck KGaA, Darmstadt, Germany and Pfizer, Inc., New York, N.Y.).
- mAbs monoclonal antibodies that bind to human PD-1
- mAbs monoclonal antibodies that bind to human PD-1
- mAbs that bind to human PD-L1 are described in WO2013/019906, WO2010/077634 A1 and U.S. Pat. No. 8,383,796.
- Specific anti-human PD-L1 mAbs useful as the PD-1 antagonist in the treatment method, medicaments and uses of the present invention include MPDL3280A, BMS-936559, MEDI4736, MSB0010718C and an antibody which comprises the heavy chain and light chain variable regions of SEQ ID NO:24 and SEQ ID NO:21, respectively, of WO2013/019906.
- PD-1 antagonists useful in any of the treatment methods, medicaments and uses of the present invention include an immunoadhesin that specifically binds to PD-1 or PD-L1, and preferably specifically binds to human PD-1 or human PD-L1, e.g., a fusion protein containing the extracellular or PD-1 binding portion of PD-L1 or PD-L2 fused to a constant region such as an Fc region of an immunoglobulin molecule.
- immunoadhesin molecules that specifically bind to PD-1 are described in WO2010/027827 and WO2011/066342.
- Specific fusion proteins useful as the PD-1 antagonist in the treatment methods, medicaments and uses of the present invention include AMP-224 (also known as B7-DCIg), which is a PD-L2-FC fusion protein that binds to human PD-1.
- one embodiment provides for a method of treating cancer comprising administering an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, in combination with a PD-1 antagonist to a subject in need thereof.
- the compounds of the invention, or a pharmaceutically acceptable salt thereof, and PD-1 antagonist are administered concurrently or sequentially.
- cancers in accordance with this embodiment include melanoma (including unresectable or metastatic melanoma), head & neck cancer (including recurrent or metastatic head and neck squamous cell cancer (HNSCC)), classical Hodgkin lymphoma (cHL), urothelial carcinoma, gastric cancer, cervical cancer, primary mediastinal large-B-cell lymphoma, microsatellite instability-high (MSI-H) cancer, non-small cell lung cancer, hepatocellular carcinoma, clear cell kidney cancer, colorectal cancer, breast cancer, squamous cell lung cancer, basal carcinoma, sarcoma, bladder cancer, endometrial cancer, pancreatic cancer, liver cancer, gastrointestinal cancer, multiple myeloma, renal cancer, mesothelioma, ovarian cancer, anal cancer, biliary tract cancer, esophageal cancer, and salivary cancer.
- HNSCC head & neck cancer
- cHL classical Hodgkin lymph
- a method of treating cancer comprising administering an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, to a person in need thereof, in combination with a PD-1 antagonist, wherein said cancer is selected from unresectable or metastatic melanoma, recurrent or metastatic head and neck squamous cell cancer (HNSCC), classical Hodgkin lymphoma (cHL), urothelial carcinoma, gastric cancer, cervical cancer, primary mediastinal large-B-cell lymphoma, microsatellite instability-high (MSI-H) cancer, non-small cell lung cancer, and hepatocellular carcinoma.
- the agent is a PD-1 antagonist.
- the agent is pembrolizumab.
- the agent is nivolumab.
- the agent is atezolizumab.
- Pembrolizumab is approved by the U.S. FDA for the treatment of patients with unresectable or metastatic melanoma and for the treatment of certain patients with recurrent or metastatic head and neck squamous cell cancer (HNSCC), classical Hodgkin lymphoma (cHL), urothelial carcinoma, gastric cancer, cervical cancer, primary mediastinal large-B-cell lymphoma, microsatellite instability-high (MSI-H) cancer, non-small cell lung cancer, and hepatocellular carcinoma, as described in the Prescribing Information for KEYTRUDATM (Merck & Co., Inc., Whitehouse Station, N.J. USA; initial U.S. approval 2014, updated November 2018).
- HNSCC head and neck squamous cell cancer
- HNSCC classical Hodgkin lymphoma
- cHL classical Hodgkin lymphoma
- MSI-H microsatellite instability-high
- non-small cell lung cancer non-small cell
- a method of treating cancer comprising administering an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, to a person in need thereof, in combination with pembrolizumab, wherein said cancer is selected from unresectable or metastatic melanoma, recurrent or metastatic head and neck squamous cell cancer (HNSCC), classical Hodgkin lymphoma (cHL), urothelial carcinoma, gastric cancer, cervical cancer, primary mediastinal large-B-cell lymphoma, microsatellite instability-high (MSI-H) cancer, non-small cell lung cancer, and hepatocellular carcinoma.
- HNSCC unresectable or metastatic melanoma
- cHL classical Hodgkin lymphoma
- MSI-H microsatellite instability-high
- a method of treating cancer comprising administering an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, to a person in need thereof, in combination with a PD-1 antagonist, wherein said cancer is selected from melanoma, non-small cell lung cancer, head and neck squamous cell cancer (HNSCC), Hodgkin lymphoma, primary mediastinal large B-cell lymphoma, urothelial carcinoma, micro satellite instability-high cancer, gastric cancer, Merkel cell carcinoma, hepatocellular carcinoma, esophageal cancer and cervical cancer.
- the agent is a PD-1 antagonist.
- the agent is pembrolizumab.
- the agent is nivolumab.
- the agent is atezolizumab.
- the agent is durvalumab.
- the agent is avelumab.
- a method of treating cancer comprising administering an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, to a person in need thereof, in combination with a PD-1 antagonist, wherein said cancer is selected from melanoma, non-small cell lung cancer, small cell lung cancer, head and neck cancer, bladder cancer, breast cancer, gastrointestinal cancer, multiple myeloma, hepatocellular cancer, lymphoma, renal cancer, mesothelioma, ovarian cancer, esophageal cancer, anal cancer, biliary tract cancer, colorectal cancer, cervical cancer, thyroid cancer, and salivary cancer.
- the agent is a PD-1 antagonist.
- the agent is pembrolizumab. In another such embodiment, the agent is nivolumab. In another such embodiment, the agent is atezolizumab. In another such embodiment, the agent is durvalumab. In another such embodiment, the agent is avelumab.
- a method of treating unresectable or metastatic melanoma comprising administering an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, to a person in need thereof, in combination with a PD-1 antagonist.
- the agent is pembrolizumab.
- the agent is nivolumab.
- the agent is atezolizumab.
- a method of treating recurrent or metastatic head and neck squamous cell cancer comprising administering an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, to a person in need thereof, in combination with a PD-1 antagonist.
- the agent is pembrolizumab.
- the agent is nivolumab.
- the agent is atezolizumab.
- a method of treating classical Hodgkin lymphoma comprising administering an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, to a person in need thereof, in combination with a PD-1 antagonist.
- the agent is pembrolizumab.
- the agent is nivolumab.
- the agent is atezolizumab.
- a method of treating urothelial carcinoma comprising administering an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, to a person in need thereof, in combination with a PD-1 antagonist.
- the agent is pembrolizumab.
- the agent is nivolumab.
- the agent is atezolizumab.
- a method of treating gastric cancer comprising administering an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, to a person in need thereof, in combination with a PD-1 antagonist.
- the agent is pembrolizumab.
- the agent is nivolumab.
- the agent is atezolizumab.
- a method of treating cervical cancer comprising administering an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, to a person in need thereof, in combination with a PD-1 antagonist.
- the agent is pembrolizumab.
- the agent is nivolumab.
- the agent is atezolizumab.
- a method of treating primary mediastinal large-B-cell lymphoma comprising administering an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, to a person in need thereof, in combination with a PD-1 antagonist.
- the agent is pembrolizumab.
- the agent is nivolumab.
- the agent is atezolizumab.
- a method of treating microsatellite instability-high (MSI-H) cancer comprising administering an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, to a person in need thereof, in combination with a PD-1 antagonist.
- the agent is pembrolizumab.
- the agent is nivolumab.
- the agent is atezolizumab.
- a method of treating non-small cell lung cancer comprising administering an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, to a person in need thereof, in combination with a PD-1 antagonist.
- the agent is pembrolizumab.
- the agent is nivolumab.
- the agent is atezolizumab.
- a method of treating hepatocellular carcinoma comprising administering an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, to a person in need thereof, in combination with a PD-1 antagonist.
- the agent is pembrolizumab.
- the agent is nivolumab.
- the agent is atezolizumab.
- the additional therapeutic agent is at least one immunomodulator other than an A2a or A2b receptor inhibitor.
- immunomodulators include CD40L, B7, B7RP1, anti-CD40, anti-CD38, anti-ICOS, 4-IBB ligand, dendritic cell cancer vaccine, IL2, IL12, ELC/CCL19, SLC/CCL21, MCP-1, IL-4, IL-18, TNF, IL-15, MDC, IFN-a/-13, M-CSF, IL-3, GM-CSF, IL-13, anti-IL-10 and indolamine 2,3-dioxygenase 1 (ID01) inhibitors.
- ID01 indolamine 2,3-dioxygenase 1
- the additional therapeutic agent comprises radiation.
- radiation includes localized radiation therapy and total body radiation therapy.
- the additional therapeutic agent is at least one chemotherapeutic agent.
- chemotherapeutic agents contemplated for use in combination with the compounds of the invention include: pemetrexed, alkylating agents (e.g., nitrogen mustards such as chlorambucil, cyclophosphamide, isofamide, mechlorethamine, melphalan, and uracil mustard; aziridines such as thiotepa; methanesulphonate esters such as busulfan; nucleoside analogs (e.g., gemcitabine); nitroso ureas such as carmustine, lomustine, and streptozocin; topoisomerase 1 inhibitors (e.g., irinotecan); platinum complexes such as cisplatin, carboplatin and oxaliplatin; bioreductive alkylators such as mitomycin, procarbazine, dacarbazine and altretamine); anthracycl
- the additional therapeutic agent is at least one signal transduction inhibitor (STI).
- signal transduction inhibitors include BCR/ABL kinase inhibitors, epidermal growth factor (EGF) receptor inhibitors, HER-2/neu receptor inhibitors, and farnesyl transferase inhibitors (FTIs).
- the additional therapeutic agent is at least one anti-infective agent.
- anti-infective agents include cytokines, non-limiting examples of which include granulocyte-macrophage colony stimulating factor (GM-CSF) and an flt3-ligand.
- the present invention provides a method for treating or preventing a viral infection (e.g., a chronic viral infection) including, but not limited to, hepatitis C virus (HCV), human papilloma virus (HPV), cytomegalovirus (CMV), Epstein-Barr virus (EBV), varicella zoster virus, coxsackievirus, and human immunodeficiency virus (HIV).
- a viral infection e.g., a chronic viral infection
- HCV hepatitis C virus
- HPV human papilloma virus
- CMV cytomegalovirus
- EBV Epstein-Barr virus
- varicella zoster virus coxsackievirus
- coxsackievirus e.g., a chronic viral infection
- HCV hepatitis C virus
- HPV human papilloma virus
- CMV cytomegalovirus
- EBV Epstein-Barr virus
- varicella zoster virus
- the present invention provides a method for the treatment of an infective disorder, said method comprising administering to a subject in need thereof an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, in combination with a vaccine.
- the vaccine is an anti-viral vaccine, including, for example, an anti-HTV vaccine.
- Other antiviral agents contemplated for use include an anti-HIV, anti-HPV, anti HCV, anti HSV agents and the like.
- the vaccine is effective against tuberculosis or malaria.
- the vaccine is a tumor vaccine (e.g., a vaccine effective against melanoma); the tumor vaccine may comprise genetically modified tumor cells or a genetically modified cell line, including genetically modified tumor cells or a genetically modified cell line that has been transfected to express granulocyte-macrophage stimulating factor (GM-CSF).
- the vaccine includes one or more immunogenic peptides and/or dendritic cells.
- the present invention provides for the treatment of an infection by administering a compound of the invention, or a pharmaceutically acceptable salt thereof, and at least one additional therapeutic agent, wherein a symptom of the infection observed after administering both the compound of the invention (or a pharmaceutically acceptable salt thereof) and the additional therapeutic agent is improved over the same symptom of infection observed after administering either alone.
- the symptom of infection observed can be reduction in viral load, increase in CD4+ T cell count, decrease in opportunistic infections, increased survival time, eradication of chronic infection, or a combination thereof.
- variable appears more than once in any moiety or in any compound of the invention (e.g., aryl, heterocycle, N(R) 2 )
- the selection of moieties defining that variable for each occurrence is independent of its definition at every other occurrence unless specified otherwise in the local variable definition.
- A2a receptor antagonist (equivalently, A2a antagonist) and/or “A2b receptor antagonist” (equivalently, A2b antagonist) means a compound exhibiting a potency (IC 50 ) of less than about 1 ⁇ M with respect to the A2a and/or A2b receptors, respectively, when assayed in accordance with the procedures described herein.
- Preferred compounds exhibit at least 10-fold selectivity for antagonizing the A2a receptor and/or the A2b receptor over any other adenosine receptor (e.g., A1 or A3).
- a compound in treatment means that an amount of the compound, generally presented as a component of a formulation that comprises other excipients, is administered in aliquots of an amount, and at time intervals, which provides and maintains at least a therapeutic serum level of at least one pharmaceutically active form of the compound over the time interval between dose administrations.
- compositions for example, “at least one pharmaceutical excipient” means that one member of the specified group is present in the composition, and more than one may additionally be present.
- Components of a composition are typically aliquots of isolated pure material added to the composition, where the purity level of the isolated material added into the composition is the normally accepted purity level for a reagent of the type.
- “Sequentially” refers to a series administration of therapeutic agents that awaits a period of efficacy to transpire between administering each additional agent; this is to say that after administration of one component, the next component is administered after an effective time period after the first component; the effective time period is the amount of time given for realization of a benefit from the administration of the first component.
- Effective amount or “therapeutically effective amount” is meant to describe the provision of an amount of at least one compound of the invention or of a composition comprising at least one compound of the invention which is effective in treating or inhibiting a disease or condition described herein, and thus produce the desired therapeutic, ameliorative, inhibitory or preventative effect.
- “effective amount” means, for example, providing the amount of at least one compound of the invention that results in a therapeutic response in a patient afflicted with the disease, condition, or disorder, including a response suitable to manage, alleviate, ameliorate, or treat the condition or alleviate, ameliorate, reduce, or eradicate one or more symptoms attributed to the condition and/or long-term stabilization of the condition, for example, as may be determined by the analysis of pharmacodynamic markers or clinical evaluation of patients afflicted with the condition.
- “Patient” and “subject” means an animal, such as a mammal (e.g., a human being) and is preferably a human being.
- Prodrug means compounds that are rapidly transformed, for example, by hydrolysis in blood, in vivo to the parent compound, e.g., conversion of a prodrug of a compound of the invention to a compound of the invention, or to a salt thereof.
- a thorough discussion is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference; the scope of this invention includes prodrugs of the novel compounds of this invention.
- substituted means that one or more of the moieties enumerated as substituents (or, where a list of substituents are not specifically enumerated, the substituents specified elsewhere in this application) for the particular type of substrate to which said substituent is appended, provided that such substitution does not exceed the normal valence rules for the atom in the bonding configuration presented in the substrate, and that the substitution ultimate provides a stable compound, which is to say that such substitution does not provide compounds with mutually reactive substituents located geminal or vicinal to each other; and wherein the substitution provides a compound sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture.
- optional substitution by a moiety means that if substituents are present, one or more of the enumerated (or default) moieties listed as optional substituents for the specified substrate can be present on the substrate in a bonding position normally occupied by the default substituent, for example, a hydrogen atom on an alkyl chain can be substituted by one of the optional substituents, in accordance with the definition of “substituted” presented herein.
- Alkyl means an aliphatic hydrocarbon group, which may be straight or branched, comprising 1 to 10 carbon atoms.
- (C 1 -C 6 )alkyl means an aliphatic hydrocarbon group, which may be straight or branched, comprising 1 to 6 carbon atoms.
- Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkyl chain.
- Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, i-butyl, and t-butyl.
- Haloalkyl means an alkyl as defined above wherein one or more hydrogen atoms on the alkyl (up to and including each available hydrogen group) is replaced by a halogen atom.
- halo or “halogen” as used herein is intended to include chloro (Cl), fluoro (F), bromo (Br) and iodo (I). Chloro (Cl) and fluoro(F) halogens are generally preferred.
- Aryl means an aromatic monocyclic or multicyclic ring system comprising 6 to 14 carbon atoms, preferably 6 to 10 carbon atoms.
- the aryl group can be optionally substituted with one or more “ring system substituents” which may be the same or different, and are as defined herein.
- suitable aryl groups include phenyl and naphthyl.
- “Monocyclic aryl” means phenyl.
- Heteroaryl means an aromatic monocyclic or multicyclic ring system comprising 5 to 14 ring atoms, preferably 5 to 10 ring atoms, in which one or more of the ring atoms is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination. Preferred heteroaryls contain 5 to 6 ring atoms.
- the “heteroaryl” can be optionally substituted by one or more substituents, which may be the same or different, as defined herein.
- the prefix aza, oxa or thia before the heteroaryl root name means that at least a nitrogen, oxygen or sulfur atom respectively, is present as a ring atom.
- heteroaryl may also include a heteroaryl as defined above fused to an aryl as defined above.
- suitable heteroaryls include pyridyl, pyrazinyl, furanyl, thienyl (which alternatively may be referred to as thiophenyl), pyrimidinyl, pyridone (including N-substituted pyridones), isoxazolyl, isothiazolyl, oxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl, 1,2,4-thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl, oxindolyl, imidazo
- heteroaryl also refers to partially saturated heteroaryl moieties such as, for example, tetrahydroisoquinolyl, tetrahydroquinolyl and the like.
- monocyclic heteroaryl refers to monocyclic versions of heteroaryl as described above and includes 4- to 7-membered monocyclic heteroaryl groups comprising from 1 to 4 ring heteroatoms, said ring heteroatoms being independently selected from the group consisting of N, O, and S, and oxides thereof. The point of attachment to the parent moiety is to any available ring carbon or ring heteroatom.
- Non-limiting examples of monocyclic heteroaryl moieties include pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, pyridazinyl, pyridinyl, thiazolyl, isothiazolyl, oxazolyl, oxadiazolyl, isoxazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl, thiadiazolyl (e.g., 1,2,4-thiadiazolyl), imidazolyl, and triazinyl (e.g., 1,2,4-triazinyl), and oxides thereof.
- thiadiazolyl e.g., 1,2,4-thiadiazolyl
- imidazolyl e.g., 1,2,4-triazinyl
- oxides thereof e.g., 1,2,4-triazinyl
- Cycloalkyl means a non-aromatic fully saturated monocyclic or multicyclic ring system comprising 3 to 10 carbon atoms, preferably 3 to 6 carbon atoms.
- the cycloalkyl can be optionally substituted with one or more substituents, which may be the same or different, as described herein.
- Monocyclic cycloalkyl refers to monocyclic versions of the cycloalkyl moieties described herein.
- suitable monocyclic cycloalkyls include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.
- Non-limiting examples of multicyclic cycloalkyls include [1.1.1]-bicyclopentane, 1-decalinyl, norbornyl, adamantyl and the like.
- Heterocycloalkyl (or “heterocyclyl”) means a non-aromatic saturated monocyclic or multicyclic ring system comprising 3 to 10 ring atoms, preferably 5 to 10 ring atoms, in which one or more of the atoms in the ring system is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination. There are no adjacent oxygen and/or sulfur atoms present in the ring system.
- Preferred heterocycloalkyl groups contain 4, 5 or 6 ring atoms.
- the prefix aza, oxa or thia before the heterocyclyl root name means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom.
- any —NH in a heterocyclyl ring may exist protected such as, for example, as an —N(Boc), —N(CBz), —N(Tos) group and the like; such protections are also considered part of this invention.
- the heterocyclyl can be optionally substituted by one or more substituents, which may be the same or different, as described herein.
- the nitrogen or sulfur atom of the heterocyclyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide.
- Heterocyclyl also includes rings wherein ⁇ O replaces two available hydrogens on the same carbon atom (i.e., heterocyclyl includes rings having a carbonyl group in the ring). Such ⁇ O groups may be referred to herein as “oxo.”
- An example of such a moiety is pyrrolidinone (or pyrrolidone):
- the term “monocyclic heterocycloalkyl” refers to monocyclic versions of the heterocycloalkyl moieties described herein and include a 4- to 7-membered monocyclic heterocycloalkyl groups comprising from 1 to 4 ring heteroatoms, said ring heteroatoms being independently selected from the group consisting of N, N-oxide, O, S, S-oxide, S(O), and S(O) 2 .
- the point of attachment to the parent moiety is to any available ring carbon or ring heteroatom.
- Non-limiting examples of monocyclic heterocycloalkyl groups include piperidyl, oxetanyl, pyrrolyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, beta lactam, gamma lactam, delta lactam, beta lactone, gamma lactone, delta lactone, and pyrrolidinone, and oxides thereof.
- Non-limiting examples of lower alkyl-substituted oxetanyl include the moiety:
- hetero-atom containing ring systems of this invention there are no hydroxyl groups on carbon atoms adjacent to a N, O or S, and there are no N or S groups on carbon adjacent to another heteroatom.
- the line as a bond generally indicates a mixture of, or either of, the possible isomers, e.g., containing (R)- and (S)-stereochemistry.
- the possible isomers e.g., containing (R)- and (S)-stereochemistry.
- the wavy line indicates a point of attachment to the rest of the compound. Lines drawn into the ring systems, such as, for example:
- Oxo is defined as an oxygen atom that is double bonded to a ring carbon in a cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, or other ring described herein, e.g.,
- One or more compounds of the invention may also exist as, or optionally be converted to, a solvate.
- Preparation of solvates is generally known.
- M. Caira et al., J. Pharmaceutical Sci., 93(3), 601-611 (2004) describe the preparation of the solvates of the antifungal fluconazole in ethyl acetate as well as from water.
- Similar preparations of solvates, and hemisolvate, including hydrates (where the solvent is water or aqueous-based) and the like are described by E. C. van Tonder et al., AAPS PharmSciTech., 5(1), article 12 (2004); and A. L. Bingham et al., Chem.
- a typical, non-limiting, process involves dissolving the inventive compound in desired amounts of the desired solvent (for example, an organic solvent, an aqueous solvent, water or mixtures of two or more thereof) at a higher than ambient temperature, and cooling the solution, with or without an antisolvent present, at a rate sufficient to form crystals which are then isolated by standard methods.
- the desired solvent for example, an organic solvent, an aqueous solvent, water or mixtures of two or more thereof
- Analytical techniques such as, for example I.R. spectroscopy, show the presence of the solvent (including water) in the crystals as a solvate (or hydrate in the case where water is incorporated into the crystalline form).
- purified refers to the physical state of said compound after being isolated from a synthetic process or natural source or combination thereof.
- purified refers to the physical state of said compound after being obtained from a purification process or processes described herein or well known to the skilled artisan, and in sufficient purity to be characterized by standard analytical techniques described herein or well known to the skilled artisan.
- This invention also includes the compounds of the invention in isolated and purified form obtained by routine techniques.
- Polymorphic forms of the compounds of the invention, and of the salts, solvates and prodrugs of the thereof, are intended to be included in the present invention.
- Certain compounds of the invention may exist in different isomeric forms (e.g., enantiomers, diastereoisomers, atropisomers).
- the inventive compounds include all isomeric forms thereof, both in pure form and admixtures of two or more, including racemic mixtures.
- presenting a structural representation of any tautomeric form of a compound which exhibits tautomerism is meant to include all such tautomeric forms of the compound. Accordingly, where compounds of the invention, their salts, and solvates and prodrugs thereof, may exist in different tautomeric forms or in equilibrium among such forms, all such forms of the compound are embraced by, and included within the scope of the invention.
- tautomers include, but are not limited to, ketone/enol tautomeric forms, imine-enamine tautomeric forms, and for example heteroaromatic forms such as the following moieties:
- reaction scheme appearing in an example employs a compound having one or more stereocenters
- the stereocenters are indicated with an asterisk, as shown below:
- the above depiction consists of the following pairs of isomers: (i) Trans-isomers ((2R,7aS)-2-methylhexahydro-1H-pyrrolizin-7a-yl)methanamine (Compound ABC-1) and ((2S,7aR)-2-methylhexahydro-1H-pyrrolizin-7a-yl)methanamine (Compound ABC-2); and (ii) Cis-isomers ((2R,7aR)-2-methylhexahydro-1H-pyrrolizin-7a-yl)methanamine (Compound ABC-3) and ((2S,7aS)-2-methylhexahydro-1H-pyrrolizin-7a-yl)methanamine (Compound ABC-4).
- All stereoisomers of the compounds of the invention include salts and solvates of the inventive compounds and their prodrugs, such as those which may exist due to asymmetric carbons present in a compound of the invention, and including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and diastereomeric forms, are contemplated within the scope of this invention.
- Individual stereoisomers of the compounds of the invention may be isolated in a pure form, for example, substantially free of other isomers, or may be isolated as an admixture of two or more stereoisomers or as a racemate.
- the chiral centers of the present invention can have the S or R configuration as defined by the IUPAC 1974 Recommendations.
- salt is intended to equally apply to salts, solvates and prodrugs of isolated enantiomers, stereoisomer pairs or groups, rotamers, tautomers, or racemates of the inventive compounds.
- diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by known methods, for example, by chiral chromatography and/or fractional crystallization, simple structural representation of the compound contemplates all diastereomers of the compound.
- enantiomers may also be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individually isolated diastereomers to the corresponding purified enantiomers.
- an appropriate optically active compound e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride
- salts of the inventive compounds whether acidic salts formed with inorganic and/or organic acids, basic salts formed with inorganic and/or organic bases, salts formed which include zwitterionic character, for example, where a compound contains both a basic moiety, for example, but not limited to, a nitrogen atom, for example, an amine, pyridine or imidazole, and an acidic moiety, for example, but not limited to a carboxylic acid, are included in the scope of the inventive compounds described herein.
- the formation of pharmaceutically useful salts from basic (or acidic) pharmaceutical compounds are discussed, for example, by S. Berge et al., Journal of Pharmaceutical Sciences (1977) 66(1) 1-19; P. Gould, International J.
- the present invention contemplates all available salts, including salts which are generally recognized as safe for use in preparing pharmaceutical formulations and those which may be formed presently within the ordinary skill in the art and are later classified as being “generally recognized as safe” for use in the preparation of pharmaceutical formulations, termed herein as “pharmaceutically acceptable salts”.
- Examples of pharmaceutically acceptable acid addition salts include, but are not limited to, acetates, including trifluoroacetate salts, adipates, alginates, ascorbates, aspartates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, cyclopentanepropionates, digluconates, dodecylsulfates, ethanesulfonates, fumarates, glucoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides, hydrobromides, hydroiodides, 2-hydroxyethanesulfonates, lactates, maleates, methanesulfonates, methyl sulfates, 2-naphthalenesulfonates, nicotinates, nitrates, oxal
- Examples of pharmaceutically acceptable basic salts include, but are not limited to, ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, aluminum salts, zinc salts, salts with organic bases (for example, organic amines) such as benzathines, diethylamine, dicyclohexylamines, hydrabamines (formed with N,N-bis(dehydroabietyl)ethylenediamine), N-methyl-D-glucamines, N-methyl-D-glucamides, t-butyl amines, piperazine, phenylcyclohexyl-amine, choline, tromethamine, and salts with amino acids such as arginine, lysine and the like.
- organic bases for example, organic amines
- organic bases for example, organic amines
- Basic nitrogen-containing groups may be converted to an ammonium ion or quarternized with agents such as lower alkyl halides (e.g. methyl, ethyl, propyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g. dimethyl, diethyl, dibutyl, and diamyl sulfates), long chain halides (e.g. decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides), arylalkyl halides (e.g. benzyl and phenethyl bromides), and others.
- lower alkyl halides e.g. methyl, ethyl, propyl, and butyl chlorides, bromides and iodides
- dialkyl sulfates e.g. dimethyl, diethyl, dibutyl, and diamyl
- a functional group in a compound termed “protected” means that the group is in modified form to preclude undesired side reactions at the protected site when the protected compound is subjected to particular reaction conditions aimed at modifying another region of the molecule.
- Suitable protecting groups are known, for example, as by reference to standard textbooks, for example, T. W. Greene et al., Protective Groups in organic Synthesis (1991), Wiley, New York.
- the atoms may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature.
- the present invention is meant to include all suitable isotopic variations of the compounds of the invention.
- different isotopic forms of hydrogen (H) include protium ( 1 H) and deuterium ( 2 H).
- Protium is the predominant hydrogen isotope found in nature. Enriching for deuterium may afford certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements, or may provide a compound useful as a standard for characterization of biological samples.
- Isotopically-enriched compounds of the invention can be prepared without undue experimentation by conventional techniques well known to those skilled in the art or by processes analogous to those described in the Schemes and Examples herein using appropriate isotopically-enriched reagents and/or intermediates.
- the present invention also embraces isotopically-labeled compounds of the present invention which are structurally identical to those recited herein, but for the fact that a statistically significant percentage of one or more atoms in that form of the compound are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number of the most abundant isotope usually found in nature, thus altering the naturally occurring abundance of that isotope present in a compound of the invention.
- isotopes that can be preferentially incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, iodine, fluorine and chlorine, for example, but not limited to: 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, and 36 Cl, 123 I and 125 I. It will be appreciated that other isotopes also may be incorporated by known means.
- Certain isotopically-labeled compounds of the invention are recognized as being particularly useful in compound and/or substrate tissue distribution assays using a variety of known techniques. Tritiated (i.e., 3 H) and carbon-14 (i.e., 14 C) isotopes are particularly preferred for their ease of preparation and detection. Further, substitution of a naturally abundant isotope with a heavier isotope, for example, substitution of protium with deuterium (i.e., 2 H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances.
- Isotopically labeled compounds of the invention can generally be prepared by following procedures analogous to those disclosed in the reaction Schemes and/or in the Examples herein below, by substituting an appropriate isotopically labeled reagent for a non-isotopically labeled reagent, or by well-known reactions of an appropriately prepared precursor to the compound of the invention which is specifically prepared for such a “labeling” reaction. Such compounds are included also in the present invention.
- composition is intended to encompass a product comprising the specified ingredients in the specified amounts, and any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
- pharmaceutical composition encompasses both the bulk composition and individual dosage units comprised of one, or more than one (e.g., two), pharmaceutically active agents such as, for example, a compound of the present invention (optionally together with an additional agent as described herein), along with any pharmaceutically inactive excipients.
- excipients are any constituent which adapts the composition to a particular route of administration or aids the processing of a composition into a dosage form without itself exerting an active pharmaceutical effect.
- the bulk composition and each individual dosage unit can contain fixed amounts of the aforesaid one, or more than one, pharmaceutically active agents.
- the bulk composition is material that has not yet been formed into individual dosage units.
- compositions of the invention may comprise more than one compound of the invention (or a pharmaceutically acceptable salt thereof), for example, the combination of two or three compounds of the invention, each present in such a composition by adding to the formulation the desired amount of the compound in a pharmaceutically acceptably pure form. It will be appreciated also that in formulating compositions of the invention, a composition may comprise, in addition to one or more of compounds of the invention, one or more other agents which also have pharmacological activity, as described herein.
- formulations of the invention may be employed in bulk form, it will be appreciated that for most applications the inventive formulations will be incorporated into a dosage form suitable for administration to a patient, each dosage form comprising an amount of the selected formulation which contains an effective amount of one or more compounds of the invention.
- suitable dosage forms include, but are not limited to, dosage forms adapted for: (i) oral administration, e.g., a liquid, gel, powder, solid or semi-solid pharmaceutical composition which is loaded into a capsule or pressed into a tablet and may comprise additionally one or more coatings which modify its release properties, for example, coatings which impart delayed release or formulations which have extended release properties; (ii) a dosage form adapted for intramuscular administration (IM), for example, an injectable solution or suspension, and which may be adapted to form a depot having extended release properties; (iii) a dosage form adapted for intravenous administration (IV), for example, a solution or suspension, for example, as an IV solution or a concentrate to be injected into a saline IV bag; (iv) a dosage form adapted for administration through tissues of the oral cavity, for example, a rapidly dissolving tablet, a lozenge, a solution, a gel, a sachets or a needle array suitable for providing intramucosal
- compositions comprising compounds of the invention
- the compounds of the invention will be combined with one or more pharmaceutically acceptable excipients.
- excipients impart to the composition properties which make it easier to handle or process, for example, lubricants or pressing aids in powdered medicaments intended to be tableted, or adapt the formulation to a desired route of administration, for example, excipients which provide a formulation for oral administration, for example, via absorption from the gastrointestinal tract, transdermal or transmucosal administration, for example, via adhesive skin “patch” or buccal administration, or injection, for example, intramuscular or intravenous, routes of administration.
- carrier typically formulations may comprise up to about 95 percent active ingredient, although formulations with greater amounts may be prepared.
- compositions can be solid, semi-solid or liquid.
- Solid form preparations can be adapted to a variety of modes of administration, examples of which include, but are not limited to, powders, dispersible granules, mini-tablets, beads, which can be used, for example, for tableting, encapsulation, or direct administration.
- Liquid form preparations include, but are not limited to, solutions, suspensions and emulsions which for example, but not exclusively, can be employed in the preparation of formulations intended for parenteral injection, for intranasal administration, or for administration to some other mucosal membrane.
- Formulations prepared for administration to various mucosal membranes may also include additional components adapting them for such administration, for example, viscosity modifiers.
- Aerosol preparations for example, suitable for administration via inhalation or via nasal mucosa, may include solutions and solids in powder form, which may be in combination with a pharmaceutically acceptable propellant, for example, an inert compressed gas, e.g. nitrogen.
- a pharmaceutically acceptable propellant for example, an inert compressed gas, e.g. nitrogen.
- solid form preparations which are intended to be converted, shortly before use, to a suspension or a solution, for example, for oral or parenteral administration. Examples of such solid forms include, but are not limited to, freeze dried formulations and liquid formulations adsorbed into a solid absorbent medium.
- transdermal compositions can take also the form of creams, lotions, aerosols and/or emulsions and can be provided in a unit dosage form which includes a transdermal patch of any know in the art, for example, a patch which incorporates either a matrix comprising the pharmaceutically active compound or a reservoir which comprises a solid or liquid form of the pharmaceutically active compound.
- the pharmaceutical preparation is in a unit dosage form.
- the preparations subdivided into suitably sized unit doses containing appropriate quantities of the active component, e.g., an effective amount to achieve the desired purpose.
- the actual dosage employed may be varied depending upon the requirements of the patient and the severity of the condition being treated. Determination of the proper dosage regimen for a particular situation is within the skill in the art. For convenience, the total daily dosage may be divided and administered in portions during the day as required.
- antagonism of adenosine A2a and/or A2b receptors is accomplished by administering to a patient in need of such therapy an effective amount of one or more compounds of the invention, or a pharmaceutically acceptable salt thereof.
- the compound in some embodiments it is preferred for the compound to be administered in the form of a pharmaceutical composition
- a pharmaceutical composition comprising the compound of the invention, or a salt thereof, and at least one pharmaceutically acceptable carrier (described herein).
- pharmaceutically formulations of the invention may comprise more than one compound of the invention, or a salt thereof, for example, the combination of two or three compounds of the invention, or, additionally or alternatively, another active agent such as those described herein, each present by adding to the formulation the desired amount of the compound or a salt thereof (or agent, where applicable) which has been isolated in a pharmaceutically acceptably pure form.
- administration of a compound of the invention to effect antagonism of A2a and/or A2b receptors is preferably accomplished by incorporating the compound into a pharmaceutical formulation incorporated into a dosage form, for example, one of the above-described dosage forms comprising an effective amount of at least one compound of the invention (e.g., 1, 2 or 3, or 1 or 2, or 1, and usually 1 compound of the invention), or a pharmaceutically acceptable salt thereof.
- a pharmaceutical formulation incorporated into a dosage form
- a dosage form for example, one of the above-described dosage forms comprising an effective amount of at least one compound of the invention (e.g., 1, 2 or 3, or 1 or 2, or 1, and usually 1 compound of the invention), or a pharmaceutically acceptable salt thereof.
- the amount and frequency of administration of the compounds of the invention and/or the pharmaceutically acceptable salts thereof will be regulated according to the judgment of the attending clinician considering such factors as age, condition and size of the patient as well as severity of the symptoms being treated.
- Compounds of the invention can be administered at a total daily dosage of up to 1,000 mg, which can be administered in one daily dose or can be divided into multiple doses per 24 hour period, for example, two to four doses per day.
- an appropriate dosage level for a compound (or compounds) of the invention will generally be about 0.01 to 500 mg per kg patient body weight per day which can be administered in single or multiple doses.
- a suitable dosage level may be about 0.01 to 250 mg/kg per day, about 0.05 to 100 mg/kg per day, or about 0.1 to 50 mg/kg per day. Within this range the dosage may be 0.05 to 0.5, 0.5 to 5 or 5 to 50 mg/kg per day.
- compositions may be provided in the form of tablets containing 1.0 to 1000 milligrams of the active ingredient, particularly 1.0, 5.0, 10.0, 15.0, 20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0, and 1000.0 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated.
- the compounds may be administered on a regimen of 1 to 4 times per day, or may be administered once or twice per day.
- treatment protocols utilizing at least one compound of the invention can be varied according to the needs of the patient.
- compounds of the invention used in the methods of the invention can be administered in variations of the protocols described above.
- compounds of the invention can be administered discontinuously rather than continuously during a treatment cycle.
- the dosage form administered will contain an amount of at least one compound of the invention, or a salt thereof, which will provide a therapeutically effective serum level of the compound in some form for a suitable period of time such as at least 2 hours, more preferably at least four hours or longer.
- dosages of a pharmaceutical composition providing a therapeutically effective serum level of a compound of the invention can be spaced in time to provide serum level meeting or exceeding the minimum therapeutically effective serum level on a continuous basis throughout the period during which treatment is administered.
- the dosage form administered may also be in a form providing an extended release period for the pharmaceutically active compound which will provide a therapeutic serum level for a longer period, necessitating less frequent dosage intervals.
- composition of the invention can incorporate additional pharmaceutically active components or be administered simultaneously, contemporaneously, or sequentially with other pharmaceutically active agents as may be additionally needed or desired in the course of providing treatment.
- dosage form administered may also be in a form providing an extended release period for the pharmaceutically active compound which will provide a therapeutic serum level for a longer period, necessitating less frequent dosage intervals.
- the compounds of the present invention can be prepared readily according to the following schemes and specific examples, or modifications thereof, using readily available starting materials, reagents and conventional synthetic procedures. In these reactions, it is also possible to make use of variants which are themselves known to those of ordinary skill in this art but are not mentioned in detail.
- the general procedures for making the compounds claimed in this invention can be readily understood and appreciated by one skilled in the art from viewing the following Schemes and descriptions.
- One general strategy for the synthesis of compounds of type G1.6 is via the four-step procedure shown in General Scheme 1, wherein R 4 corresponds to ring A in Formula (I) and wherein R 1 , R 2 , and ring A are as defined in Formula (I).
- amino benzonitriles G1.1 can be treated with 1-(isocyanatomethyl)-2,4-dimethoxybenzene in solvents such as the combination of dichloromethane and pyridine to form intermediate ureas G1.2.
- these ureas can be dehydrated to the corresponding carbodiimides G1.3 in the presence of triphenylphosphine, carbon tetrabromide, and triethylamine in a solvent such as dichloromethane.
- a hydrazide of the type G1.4 in the presence of acetic acid in a solvent such as dichloromethane or dioxane, produces products of the type G1.5.
- the 2,4-dimethoxybenzyl group of G1.4 is removed under acidic conditions to provide products of type G1.6, which can be purified by silica gel chromatography, preparative reversed phase HPLC, and/or chiral SFC.
- R A (n) corresponds to R A1 , R A2 , R A3 , and R A5 in Formula (I) and wherein R 1 , R 2 , R 3 and R A(n) (as R A1 , R A2 , R A3 , and R A5 ) are as defined in Formula (I).
- protected cyclic amines G2.1 can be converted into unprotected amines G2.2 through carefully controlled treatment with acid. Acids such as formic acid in the absence of solvent or hydrochloric acid in the presence of MeOH or DCM, can be used.
- intermediates of type G2.2 can be converted into intermediates of type G2.4 through a transition-metal catalyzed C—N coupling reaction with aryl bromides G2.3.
- the reaction is performed under deoxygenated conditions with palladium catalysts such as, tert-butyl X-Phos Third Generation Precatalyst, a base such as sodium tert-butoxide, and a solvent such as THF, at the appropriate temperature.
- the 2,4-dimethoxybenzyl group of G2.4 is removed under acidic conditions to provide products of type G2.5, which can be purified by silica gel chromatography, preparative reversed-phase HPLC, and/or chiral SFC.
- One general strategy for the synthesis of compounds of type G3.6 is via a four-step procedure shown in General Scheme 3, wherein R 4 corresponds to ring A in Formula (I) and wherein R 1 , R 2 , and ring A are as defined in Formula (I).
- amino benzoic acids G3.1 can be converted into amino quinazolines G3.2 via treatment with cyanamide in the presence of aqueous HCl in a solvent such as EtOH.
- intermediates of type G3.2 can be converted into intermediates of type G3.3 through coupling with 1,2,4-triazole, following treatment of G3.2 with phosphorous (V) oxychloride in a solvent such as acetonitrile.
- intermediates of type G3.3 can be treated with hydrazides G3.4 in a solvent such as THF, to provide products of type G3.5.
- intermediates of type G3.5 can undergo a rearrangement upon heating in neat N,O-Bis(trimethylsilyl)acetamide (BSA) to form products of type G3.6.
- BSA N,O-Bis(trimethylsilyl)acetamide
- Products of type G3.6 can be purified by silica gel chromatography, preparative reversed-phase HPLC, and/or chiral SFC.
- One general strategy for the synthesis of compounds of type G4.5 is via a three-step procedure outlined in General Scheme 4, wherein R 1 , R 2 , R 3 , R A1 , R A2 , and R A3 are defined in Formula (I).
- Heteroaryl cyclohexanol G4.1 can be converted into the corresponding cyclohexanone G4.2 via oxidation with Dess-Martin periodinane.
- intermediates of type G4.2 can undergo treatment with an R 3 —Li G4.3 at low temperature, to provide products of type G4.4.
- the 2,4-dimethoxybenzyl group of G2.4 can be removed with DDQ to provide products of type G4.5, which can be purified by silica gel chromatography, preparative reversed-phase HPLC, and/or chiral SFC.
- diethyl ether used in the experiments described below was Fisher ACS certified material and stabilized with BHT.
- degassed refers to a solvent from which oxygen has been removed, generally by bubbling an inert gas such as nitrogen or argon through the solution for 10 to 15 minutes with an outlet needle to normalize pressure.
- concentrated means evaporating the solvent from a solution or mixture using a rotary evaporator or vacuum pump.
- evaporated means evaporating using a rotary evaporator or vacuum pump.
- silica gel chromatography was carried out on an ISCO®, Analogix®, or Biotage® automated chromatography system using a commercially available cartridge as the column. Columns were usually filled with silica gel as the stationary phase. Reverse phase preparative HPLC conditions can be found at the end of the experimental section. Aqueous solutions were concentrated on a Genevac® evaporator or were lyophilized.
- proton nuclear magnetic resonance ( 1 H NMR) spectra and proton-decoupled carbon nuclear magnetic resonance ( 13 C ⁇ 1 H ⁇ NMR) spectra were recorded on 400, 500, or 600 MHz Bruker or Varian NMR spectrometers at ambient temperature. All chemical shifts (6) were reported in parts per million (ppm).
- Proton resonances were referenced to residual protium in the NMR solvent, which can include, but is not limited to, CDCl 3 , DMSO-d 6 , and MeOD-d 4 .
- Carbon resonances are referenced to the carbon resonances of the NMR solvent.
- Step 1 of the synthesis of Intermediate 12 was conducted similar to step 1 of the synthesis of Intermediate 11 from the appropriate starting materials to afford (3-methyloxetan-3-yl)methyl methanesulfonate.
- Step 1 4-bromo-1-(5,8-dioxaspiro[3.4]octan-2-yl)-1H-pyrazole
- Step 1 of the synthesis of Intermediate 21 was conducted in manner similar to that used in the synthesis of Intermediate 1 from the appropriate starting materials to afford 1-(3-cyclopropyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol.
- Step 1 of the synthesis of Intermediate 22 was conducted in a manner analogous to step 2 of the synthesis of Intermediate 21 from the appropriate starting materials to afford (4-bromo-1-ethyl-1H-pyrazol-3-yl)methanol.
- LCMS C 6 H 9 BrN 2 O
- ES m/z
- Step 2 rac-4-bromo-1-ethyl-3-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-pyrazole
- Step 1 rac-(1-((tetrahydro-2H-pyran-2-yl)oxy)cyclobutyl)methyl methanesulfonate
- Step 2 rac-4-bromo-1-((1-((tetrahydro-2H-pyran-2-yl)oxy)cyclobutyl)methyl)-1H-pyrazole
- Methylmagnesium bromide (0.248 ml, 0.744 mmol, 3 M in diethyl ether) was added to a stirred mixture of rac-2-(4-bromo-1H-pyrazol-1-yl)cyclobutanone (Intermediate 28) (80.0 mg, 0.372 mmol) in THF (2 mL) at ⁇ 78° C., and the mixture was stirred at that temperature for 3 h. The reaction was quenched with aqueous saturated NH 4 Cl (2 mL), and the desired layer was extracted from the mixture with EtOAc (2 ⁇ 20 mL). The combined organic layers were dried over anhydrous Na 2 SO 4 , filtered, and evaporated.
- Step 1 ethyl 2-methyl-2-(4-nitro-1H-pyrazol-1-yl)propanoate
- Step 3 of the synthesis of Intermediate 34 was conducted in a manner similar to that of step 2 of the synthesis of Intermediate 33, using 2-methyl-2-(4-nitro-1H-pyrazol-1-yl) propan-1-ol as the starting material, to afford 2-(4-amino-1H-pyrazol-1-yl)-2-methylpropan-1-ol.
- LCMS C 7 H 13 N 3 O
- ES m/z
- Step 1 1-(2-Cyano-4-fluoro-5-methoxyphenyl)-3-(2,4-dimethoxybenzyl)urea
- Step 1 of the synthesis of Intermediate 46 was conducted in a manner similar to that of step 1 of the synthesis of Intermediate 45 from the appropriate starting materials to afford methyl 4-methylpiperidine-3-carboxylate.
- LCMS C 8 H 15 NO 2
- ES m/z
- Step 2 of the synthesis of Intermediate 46 was conducted in a manner similar to step 2 of the synthesis of Intermediate 45 from the appropriate starting materials, with the exception that the crude material was purified by silica gel chromatography with 0-30% EtOAc in petroleum ether as eluent to afford to 1-(tert-butyl) 3-methyl 4-methylpiperidine-1,4-dicarboxylate.
- Intermediate 47 mixture of rac,cis-1-(tert-butyl) 3-ethyl-5-fluoropiperidine-1,3-dicarboxylate and rac,trans-1-(tert-butyl) 3-ethyl-5-fluoropiperidine-1,3-dicarboxylate
- racemic mixture was resolved by chiral SFC (Chiral Technologies AD-H 21 ⁇ 250 mm column with 15% (MeOH w/0.1% NH 4 OH modifier) as cosolvent), to afford methyl (3S,6R)-1-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-6-methylpiperidine-3-carboxylate (Intermediate 48, first eluting peak) and methyl (3R,6S)-1-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-6-methylpiperidine-3-carboxylate (Intermediate 49, second eluting peak).
- Step 2 rac-diethyl 2-(3-((1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)amino)pentyl)malonate
- Step 3 ethyl 6-ethyl-1-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-2-oxopiperidine-3-carboxylate
- Step 1 ethyl 1-(1-methyl-1H-pyrazol-4-yl)piperidine-3-carboxylate
- racemic mixture was resolved by chiral SFC separation (Chiral Technologies AD-H 21 ⁇ 250 mm column with 40% (MeOH w/0.25% DEA modifier) as co-solvent to afford (R or S)-1-(1-methyl-1H-pyrazol-4-yl)piperidine-3-carbohydrazide as the first eluting peak and (S or R)-1-(1-methyl-1H-pyrazol-4-yl)piperidine-3-carbohydrazide as the second eluting peak corresponding to Intermediate 67a and Intermediate 67b, respectively.
- LCMS C 10 H 17 N 5 O
- Step 1 (R)-tert-butyl 3-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidine-1-carboxylate
- Step 2 (R)—N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-(piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine
- Step 1 rac-benzyl 3-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-7-methoxy-[ 1,2,4]triazolo[1,5-c]quinazolin-2-yl)-3-fluoropiperidine-1-carboxylate
- Step 2 (S or R)—N-(2,4-dimethoxybenzyl)-9-fluoro-2-(3-fluoropiperidin-3-yl)-7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-5-amine and (R or S)—N-(2,4-dimethoxybenzyl)-9-fluoro-2-(3-fluoropiperidin-3-yl)-7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-5-amine
- Step 1 tert-butyl (R)-3-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidine-1-carboxylate
- Step 2 (R)—N-(2,4-dimethoxybenzyl)-9-fluoro-7-methoxy-2-(piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine
- POCl 3 (295 ⁇ L, 3.16 mmol) was added dropwise over 15 min to a stirred mixture of 1,2,4-triazole (524 mg, 7.59 mmol), 2-amino-6-fluoro-8-methoxyquinazolin-4-ol (264.7 mg, 1.265 mmol), and DIPEA (553 ⁇ L, 3.16 mmol) in acetonitrile (5 mL) at room temperature. The mixture was stirred and heated at 40° C. for 3 h and then at room temperature for 16 h. The mixture was filtered through Celite® (diatomaceous earth).
- Step 3 rac-N′-(2-amino-6-fluoro-8-methoxyquinazolin-4-yl)-1-(1-methyl-1H-pyrazol-4-yl)piperidine-3-carbohydrazide
- Step 1 3-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-6-ethyl-1-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)piperidin-2-one
- Step 2 1-(4-((2R or 2S,5S or 5R)-5-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-ethylpiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol and 1-(4-((2S or 2R,5R or 55)-5-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-ethylpiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol and 1-(4-((2S or 2R,5S or 5R)-5-(5-((2,4-dimeth
- the first eluting racemate was resolved by chiral SFC separation (Chiral Technologies, AS-H, 21 ⁇ 250 mm column with 50% (IPA+0.2% DIPA) as co-solvent) to afford 1-(4-((2R or 2S,5S or 5R)-5-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-ethylpiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol (first eluting peak) and 1-(4-((2S or 2R,5R or 55)-5-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-ethylpiperidin
- the second eluting racemate was resolved by chiral SFC separation (AS-H, 21 ⁇ 250 mm column with 50% (IPA+0.2% DIPA) as co-solvent) to afford 1-(4-((2S or 2R,5S or 5R)-5-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-ethylpiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol (first eluting peak) and 1-(4-((2R or 2S,5R or 5S)-5-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-ethylpiperidin-1-yl
- Step 1 mixture of (R)—N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-(1-(5-methyl-1-trityl-1H-pyrazol-4-yl)piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine and (R)—N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-(1-(3-methyl-1-trityl-1H-pyrazol-4-yl)piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine
- Step 2 Mixture of (R)—N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-(1-(3-methyl-1H-pyrazol-4-yl)piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine and (R)—N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-(1-(5-methyl-1H-pyrazol-4-yl)piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine
- the mixture was stirred and heated at 80° C. for 12 h.
- the mixture was cooled, diluted with EtOAc (10 mL), and washed with water (10 mL).
- the organic layer was dried over anhydrous Na 2 SO 4 , filtered, and the solvents of the filtrate were evaporated.
- Step 1 N-(2,4-dimethoxybenzyl)-2-((3R)-1-(1-(2,2-dimethoxycyclobutyl)-1H-pyrazol-4-yl)piperidin-3-yl)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-5-amine
- Step 2 2-(4-((R)-3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidin-1-yl)-1H-pyrazol-1-yl)cyclobutan-1-one
- Step 1 3-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)cyclohexan-1-ol
- Step 2 3-(5-((2,4-Dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)cyclohexan-1-one
- Step 3 3-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-1-(1-ethyl-1H-pyrazol-4-yl)cyclohexan-1-ol
- Step 4 rac-(1R or 1S,3R or 35)-3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-1-(1-ethyl-1H-pyrazol-4-yl)cyclohexan-1-ol and rac-(15 or 1R,3S or 3R)-3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-1-(1-ethyl-1H-pyrazol-4-yl)cyclohexan-1-ol
- the mixture was diluted with DCM (10 mL) and was washed with Na 2 SO 3 (2 M aqueous solution, 5 mL) and brine (2 ⁇ 10 mL). The organic layer was dried over anhydrous Na 2 SO 4 , filtered, and the solvents of the filtrate were evaporated.
- Step 1 methyl (3R,6S and 3S,6R)-1-(1-(2-((tert-butoxycarbonyl)amino)-2-methylpropyl)-1H-pyrazol-4-yl)-6-methylpiperidine-3-carboxylate
- Step 2 tert-butyl (1-(4-((2S,5R and 2R,5S)-5-(hydrazinecarbonyl)-2-methylpiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-yl)carbamate
- Step 1 methyl 4-methyl-2-methylene-5-oxopentanoate
- Step 2 methyl (3R,5R and 3S,5S)-1-(1-(2-hydroxy-2-methylpropyl)-5-methyl-1H-pyrazol-4-yl)-5-methylpiperidine-3-carboxylate
- Step 3 Mixture of methyl (3S,5R and 3R,5S)-1-(1-(2-hydroxy-2-methylpropyl)-5-methyl-1H-pyrazol-4-yl)-5-methylpiperidine-3-carboxylate and methyl (3R,5R and 3S,5S)-1-(1-(2-hydroxy-2-methylpropyl)-5-methyl-1H-pyrazol-4-yl)-5-methylpiperidine-3-carboxylate
- Methyl (3R,5R and 3S,5S)-1-(1-(2-hydroxy-2-methylpropyl)-5-methyl-1H-pyrazol-4-yl)-5-methylpiperidine-3-carboxylate (1.39 g, 4.49 mmol) was stirred in MeOH (35.9 ml) with potassium tert-butoxide (1.01 g, 8.98 mmol) for 18 h at 60° C. The mixture was cooled to room temperature, and the solvents were evaporated. The resulting residue was dissolved in DCM and quenched with saturated aqueous NH 4 Cl. The layers were separated using a Biotage Isolute® phase separator and the DCM layer was concentrated.
- Step 4 (3R,5S and 3S,5R)-1-(1-(2-hydroxy-2-methylpropyl)-5-methyl-1H-pyrazol-4-yl)-5-methylpiperidine-3-carbohydrazide and (3R,5R and 3S,5S)-1-(1-(2-hydroxy-2-methylpropyl)-5-methyl-1H-pyrazol-4-yl)-5-methylpiperidine-3-carbohydrazide
- step 3 To a solution of the product from step 3 (1.18 g, 3.81 mmol) in ethanol (15.3 mL) was added hydrazine hydrate (1.87 mL, 38.1 mmol). The mixture was stirred and heated at 80° C. for 16 h.
- Step 1 tert-butyl (3R,5S and 3S,5R)-3-(5-((2,4-dimethoxybenzyl)amino)-7,9-difluoro-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-methylpiperidine-1-carboxylate and tert-butyl (3S,5S and 3R,5R)-3-(5-((2,4-dimethoxybenzyl)amino)-7,9-difluoro-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-methylpiperidine-1-carboxylate
- Step 2 N-(2,4-dimethoxybenzyl)-7,9-difluoro-2-((3R,5S and 3S,5R)-5-methylpiperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine and N-(2,4-dimethoxybenzyl)-7,9-difluoro-2-((3S,5S and 3R,5R)-5-methylpiperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine
- Step 2 methyl (2-cyano-5-(difluoromethoxy)-4-fluorophenyl)carbamate
- Step 3 (R)-tert-butyl-3-(8-(difluoromethoxy)-9-fluoro-5-hydroxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidine-1-carboxylate
- Step 4 tert-butyl-3-(8-(difluoromethoxy)-5-((2,4-dimethoxybenzyl)amino)-9-fluoro-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidine-1-carboxylate
- Step 5 (R)-8-(difluoromethoxy)-N-(2,4-dimethoxybenzyl)-9-fluoro-2-(piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine
- Example compounds of the invention in the following Table 15 were prepared in a manner similar to that described in Example 1, from the appropriate starting aryl halide and amine intermediates.
- Example 40 1-((4-((2S,5R or 2R,5S)-5-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-1H-pyrazol-1-yl)methyl)cyclobutan-1-ol
- Step 1 N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-((3R,6S or 3S,6R)-6-methyl-1-(1-((1-(((RS)-tetrahydro-2H-pyran-2-yl)oxy)cyclobutyl)methyl)-1H-pyrazol-4-yl)piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine
- Step 2 1-((4-((2S,5R or 2R,5S)-5-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-1H-pyrazol-1-yl)methyl)cyclobutan-1-ol
- Example compounds of the invention in the following Table 16 were prepared in a manner similar to that described for the preparation of Example 40 from the appropriate starting aryl halide and Intermediate 95.
- Example 48 and Example 49 (R or S)-3-(4-((2S,5R or 2R,5S)-5-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylbutan-2-ol and (S or R)-3-(4-((2S,5R or 2R,5S)-5-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylbutan-2-ol
- Step 1 (R or S)-3-(4-((2S,5R or 2R,5S)-5-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylbutan-2-ol and (S or R)-3-(4-((2S,5R or 2R,5S)-5-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylbutan-2-ol
- Step 1 of the synthesis of Example 48 and Example 49 was conducted with Intermediate 95 and Intermediate 1 in a manner similar to that described in step 1 of the synthesis of Example 40.
- the resulting diastereomeric mixture was purified by SFC (Chiral Technologies AD-H 21 ⁇ 250 mm column with 55% (IPA+0.2% DIPA) as co-solvent), to afford peak 1 and peak 2 corresponding to (R or S)-3-(4-((2S,5R or 2R,5S)-5-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylbutan-2-ol and (S or R)-3-(4-((2S,5R or 2R,5S)-5-(5-((2,4-dimethoxybenzyl)a
- Step 2 (R or S)-3-(4-((2S,5R or 2R,5S)-5-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylbutan-2-ol and (S or R)-3-(4-((2S,5R or 2R,5S)-5-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylbutan-2-ol
- Step 2 of the synthesis of Example 48 and Example 49 was conducted in a manner similar to that described in step 2 of Example 40, where peak 1 was converted to (R or S)-3-(4-((2S,5R or 2R,5S)-5-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylbutan-2-ol (Example 48) and peak 2 was converted to (S or R)-3-(4-((2S,5R or 2R,5S)-5-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylbutan-2-ol (Example 49).
- Example 48 LCMS (C 24 H 31 FN 8 O 2 ) (ES, m/z): 483 [M+H] + .
- Example 50 and Example 51 1-((4-((2R,5S or 2S,5R)-5-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-3-methyl-1H-pyrazol-1-yl)methyl)cyclobutan-1-ol and 1-((4-((2R,5S or 2S,5R)-5-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-5-methyl-1H-pyrazol-1-yl)methyl)cyclobutan-1-ol
- Step 1 N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-((3S,6R or 3R,6S)-6-methyl-1-(3-methyl-1-((1-(((RS)-tetrahydro-2H-pyran-2-yl)oxy)cyclobutyl)methyl)-1H-pyrazol-4-yl)piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine and N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-((3S,6R, or 3R,6S)-6-methyl-1-(5-methyl-1-((1-((RS)-tetrahydro-2H-pyran-2-yl)oxy)cyclobutyl)methyl)-1H-pyrazol-4-yl)piperidin-3-yl)-[1,2,4]triazolo[1,5-c]
- Step 2 1-((4-((2R,5S or 2S,5R)-5-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-3-methyl-1H-pyrazol-1-yl)methyl)cyclobutan-1-ol and 1-((4-((2R,5S or 2S,5R)-5-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-5-methyl-1H-pyrazol-1-yl)methyl)cyclobutan-1-ol
- Example 50 LCMS (C 25 H 31 FN 8 O 2 ) (ES, m/z): 495 [M+H] + .
- Example 51 LCMS (C 25 H 31 FN 8 O 2 ) (ES, m/z): 495 [M+H] + .
- Example compounds of the invention in the following Table 17 were prepared in a manner similar to that described for Example 50 and Example 51 from the appropriate starting aryl halide and Intermediate 96.
- Example 54 1-((4-((3R,5S or 3S,5R)-3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-fluoropiperidin-1-yl)-1H-pyrazol-1-yl)methyl)cyclobutan-1-ol
- Step 1 N-(2,4-dimethoxybenzyl)-9-fluoro-2-((3R,5S or 3S,5R)-5-fluoro-1-(1-((1-((tetrahydro-2H-pyran-2-yl)oxy)cyclobutyl)methyl)-1H-pyrazol-4-yl)piperidin-3-yl)-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-5-amine
- Step 2 1-((4-((3R,5S or 3S,5R)-3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-fluoropiperidin-1-yl)-1H-pyrazol-1-yl)methyl)cyclobutan-1-ol
- Example compounds of the invention in the following Table 18 were prepared in a manner similar to that described for the preparation of Example 54 from the appropriate starting aryl halide and Intermediate 99.
- Example 57 1-((4-((1R,5R or 1S,5S)-1-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-1H-pyrazol-1-yl)methyl)cyclobutan-1-ol
- Step 1 N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-((1R,5R or 1S,5S)-3-(1-((1-((tetrahydro-2H-pyran-2-yl)oxy)cyclobutyl)methyl)-1H-pyrazol-4-yl)-3-azabicyclo[3.1.0]hexan-1-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine
- Step 2 1-((4-((1R,5R or 1S,5S)-1-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-1H-pyrazol-1-yl)methyl)cyclobutan-1-ol 2,2,2-trifluoroacetate
- Example 58 in the following Table 19 was prepared in a manner similar to that described for the preparation of Example 57 from Intermediate 97 and the appropriate starting aryl halide.
- Example 59 9-fluoro-2-((3S,5R or 3R,5S)-5-fluoro-1-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)piperidin-3-yl)-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-5-amine
- Step 1 N-(2,4-dimethoxybenzyl)-9-fluoro-2-((3S,5R or 3R,5S)-5-fluoro-1-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)piperidin-3-yl)-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-5-amine
- N-(2,4-dimethoxybenzyl)-9-fluoro-2-((3S,5R or 3R,5S)-5-fluoropiperidin-3-yl)-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-5-amine (Intermediate 100) (50.0 mg, 0.103 mmol), tBuXPhos-Pd G3 (24.6 mg, 0.0310 mmol), 4-bromo-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole (Intermediate 15) (23.9 mg, 0.103 mmol), sodium tert-butoxide (59.5 mg, 0.619 mmol) and THF (1 mL).
- Step 2 9-fluoro-2-((3S,5R or 3R,5S)-5-fluoro-1-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)piperidin-3-yl)-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-5-amine
- N-(2,4-dimethoxybenzyl)-9-fluoro-2-((3S,5R or 3R,5S)-5-fluoro-1-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)piperidin-3-yl)-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-5-amine 85.0 mg, 0.130 mmol
- TFA 2 mL
- Example 60 and Example 61 (R or 5)-1-(4-(3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)azepan-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol and (S or R)-1-(4-(3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)azepan-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol
- racemic mixture was resolved by chiral SFC separation (Chiral Technologies OJ-H 21 ⁇ 250 mm column with 25% (isopropanol w/0.1% NH 4 OH modifier) as co-solvent), to afford (R or S)-1-(4-(3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)azepan-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol (Example 60, first eluting peak) and (S or R)-1-(4-(3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)azepan-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol (Example 61, second eluting peak).
- Example 60 LCMS (C 23 H 29 FN 8 O 2 ) (ES, m/z): 469 [M+H] + .
- Example 61 LCMS (C 23 H 29 FN 8 O 2 ) (ES, m/z): 469 [M+H] + .
- Example compounds of the invention in the following Table 20 were prepared in a manner similar to that described for the preparation of Example 60 and Example 61 from the appropriate starting amine and aryl halide, where the resulting isomeric mixture of the corresponding final compounds were separated by SFC.
- Example 68 and Example 69 1-(4-((3R,5S or 3S,5R)-3-(5-amino-9-fluoro-7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-fluoropiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol and 1-(4-((3S,5R or 3R,5S)-3-(5-amino-9-fluoro-7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-fluoropiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol and 1-(4-((3S,5R or 3R,5S)-3-(5-amino-9-fluoro-7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin
- Step 1 rac-1-(4-((3R,5S or 3S,5R)-3-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-fluoropiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol
- Step 2 1-(4-((3R,5S or 3S,5R)-3-(5-amino-9-fluoro-7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-fluoropiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol and 1-(4-((3S,5R or 3R,55)-3-(5-amino-9-fluoro-7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-fluoropiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol and 1-(4-((3S,5R or 3R,55)-3-(5-amino-9-fluoro-7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-
- Example 68 LCMS (C 22 H 26 F 2 N 8 O 2 ) (ES, m/z): 473 [M+H] + .
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Immunology (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Epidemiology (AREA)
- Biophysics (AREA)
- Biochemistry (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Description
- The present invention relates to novel compounds that inhibit at least one of the A2a and A2b adenosine receptors, and pharmaceutically acceptable salts thereof, and compositions comprising such compound(s) and salts, methods for the synthesis of such compounds, and their use in the treatment of a variety of diseases, conditions, or disorders that are mediated, at least in part, by the adenosine A2a receptor and/or the adenosine A2b receptor. Such diseases, conditions, and disorders include but are not limited to cancer and immune-related disorders. The invention further relates to combination therapies, including but not limited to a combination comprising a compound of the invention and a PD-1 antagonist.
- Adenosine is a purine nucleoside compound comprised of adenine and ribofuranose, a ribose sugar molecule. Adenosine occurs naturally in mammals and plays important roles in various biochemical processes, including energy transfer (as adenosine triphosphate and adenosine monophosphate) and signal transduction (as cyclic adenosine monophosphate). Adenosine also plays a causative role in processes associated with vasodilation, including cardiac vasodilation. It also acts as a neuromodulator (e.g., it is thought to be involved in promoting sleep). In addition to its involvement in these biochemical processes, adenosine is used as a therapeutic antiarrhythmic agent to treat supraventricular tachycardia and other indications.
- The adenosine receptors are a class of purinergic G protein-coupled receptors with adenosine as the endogenous ligand. The four types of adenosine receptors in humans are referred to as A1, A2a, A2b, and A3. Modulation of A1 has been proposed for the management and treatment of neurological disorders, asthma, and heart and renal failure, among others. Modulation of A3 has been proposed for the management and treatment of asthma and chronic obstructive pulmonary diseases, glaucoma, cancer, stroke, and other indications. Modulation of the A2a and A2b receptors are also believed to be of potential therapeutic use.
- In the central nervous system, A2a antagonists are believed to exhibit antidepressant properties and to stimulate cognitive functions. A2a receptors are present in high density in the basal ganglia, known to be important in the control of movement. Hence, A2a receptor antagonists are believed to be useful in the treatment of depression and to improve motor impairment due to neurodegenerative diseases such as Parkinson's disease, senile dementia (as in Alzheimer's disease), and in various psychoses of organic origin.
- In the immune system, adenosine signaling through A2a receptors and A2b receptors, expressed on a variety of immune cells and endothelial cells, has been established as having an important role in protecting tissues during inflammatory responses. In this way (and others), tumors have been shown to evade host responses by inhibiting immune function and promoting tolerance. (See, e.g., Fishman, P., et al., Handb. Exp. Pharmacol. (2009) 193:399-441). Moreover, A2a and A2b cell surface adenosine receptors have been found to be upregulated in various tumor cells. Thus, antagonists of the A2a and/or A2b adenosine receptors represent a new class of promising oncology therapeutics. For example, activation of A2a adenosine receptors results in the inhibition of the immune response to tumors by a variety of cell types, including but not limited to: the inhibition of natural killer cell cytotoxicity, the inhibition of tumor-specific CD4+/CD8+ activity, promoting the generation of LAG-3 and Foxp3+ regulatory T-cells, and mediating the inhibition of regulatory T-cells. Adenosine A2a receptor inhibition has also been shown to increase the efficacy of PD-1 inhibitors through enhanced anti-tumor T cell responses. As each of these immunosuppressive pathways has been identified as a mechanism by which tumors evade host responses, a cancer immunotherapeutic regimen that includes an antagonist of the A2a and/or A2b receptors, alone or together with one or more other therapeutic agents designed to mitigate immune suppression, may result in enhanced tumor immunotherapy. (See, e.g., P. Beavis, et al., Cancer Immunol. Res. DOI: 10.1158/2326-6066. CIR-14-0211, Feb. 11, 2015; Willingham, S B., et al., Cancer Immunol. Res., 6(10), 1136-49; and Leone R D, et al., Cancer Immunol. Immunother., August 2018, Vol. 67, Issue 8, 1271-1284).
- Cancer cells release ATP into the tumor microenvironment when treated with chemotherapy and radiation therapy, which is subsequently converted to adenosine. (See Martins, I., et al., Cell Cycle, vol. 8, issue 22, pp. 3723 to 3728.) The adenosine can then bind to A2a receptors and blunt the anti-tumor immune response through mechanisms such as those described above. The administration of A2a receptor antagonists during chemotherapy or radiation therapy has been proposed to lead to the expansion of the tumor-specific T-cells while simultaneously preventing the induction of tumor-specific regulatory T-cells. (Young, A., et al., Cancer Discovery (2014) 4:879-888).
- The combination of an A2a receptor antagonist with anti-tumor vaccines is believed to provide at least an additive therapeutic effect in view of their different mechanisms of action. Further, A2a receptor antagonists may be useful in combination with checkpoint blockers. By way of example, the combination of a PD-1 inhibitor and an adenosine A2a receptor inhibitor is thought to mitigate the ability of tumors to inhibit the activity of tumor-specific effector T-cells. (See, e.g., Willingham, S B., et al., Cancer Immunol. Res.; 6(10), 1136-49; Leone, R D., et al., Cancer Immunol. Immunother., August 2018, Vol. 67, Issue 8, pp. 1271-1284; Fishman, P., et al., Handb. Exp. Pharmacol. (2009) 193:399-441; and Sitkovsky, M V., et al., (2014) Cancer Immunol. Res 2:598-605.)
- The A2b receptor is a G protein-coupled receptor found in various cell types. A2b receptors require higher concentrations of adenosine for activation than the other adenosine receptor subtypes, including A2a. (Fredholm, B B., et al., Biochem. Pharmacol. (2001) 61:443-448). Conditions which activate A2b have been seen, for example, in tumors where hypoxia is observed. The A2b receptor may thus play an important role in pathophysiological conditions associated with massive adenosine release. While the pathway(s) associated with A2b receptor-mediated inhibition are not well understood, it is believed that the inhibition of A2b receptors (alone or together with A2a receptors) may block pro-tumorigenic functions of adenosine in the tumor microenvironment, including suppression of T-cell function and angiogenesis, and thus expand the types of cancers treatable by the inhibition of these receptors.
- A2b receptors are expressed primarily on myeloid cells. The engagement of A2b receptors on myeloid derived suppressor cells (MDSCs) results in their expansion in vitro (Ryzhov, S. et al., J. Immunol. 2011, 187:6120-6129). MDSCs suppress T-cell proliferation and anti-tumor immune responses. Selective inhibitors of A2b receptors and A2b receptor knockouts have been shown to inhibit tumor growth in mouse models by increasing MDSCs in the tumor microenvironment (Iannone, R., et al., Neoplasia Vol. 13 No. 12, (2013) pp. 1400-1409; Ryzhov, S., et al., Neoplasia (2008) 10: 987-995). Thus, A2b receptor inhibition has become an attractive biological target for the treatment of a variety of cancers involving myeloid cells. Examples of cancers that express A2b receptors can be readily obtained through analysis of the publicly available TCGA database. Such cancers include lung, colorectal, head and neck, and cervical cancer, among others, and are discussed in further detail below.
- Angiogenesis plays an important role in tumor growth. The angiogenesis process is highly regulated by a variety of factors and is triggered by adenosine under particular circumstances that are associated with hypoxia. The A2b receptor is expressed in human microvascular endothelial cells, where it plays an important role in the regulation of the expression of angiogenic factors such as the vascular endothelial growth factor (VEGF). In certain tumor types, hypoxia has been observed to cause an upregulation of the A2b receptors, suggesting that inhibition of A2b receptors may limit tumor growth by limiting the oxygen supply to the tumor cells. Furthermore, experiments involving adenylate cyclase activation indicate that A2b receptors are the sole adenosine receptor subtype in certain tumor cells, suggesting that A2b receptor antagonists may exhibit effects on particular tumor types. (See, e.g., Feoktistov, I., et al., (2003) Circ. Res. 92:485-492; and P. Fishman, P., et al., Handb. Exp. Pharmacol. (2009) 193:399-441).
- In view of their promising and varied therapeutic potential, there remains a need in the art for potent and selective inhibitors of the A2a and/or A2b adenosine receptors, for use alone or in combination with other therapeutic agents. The present invention addresses this and other needs.
- In one aspect, the present invention provides compounds (hereinafter referred to as compounds of the invention) which, surprisingly and advantageously, have been found to be inhibitors of the adenosine A2a receptor and/or the adenosine A2b receptor. The compounds of the invention have a structure in accordance with the structural Formula (I):
- or a pharmaceutically acceptable salt thereof, wherein ring A, R1, and R2 are as defined below.
- In another aspect, the present invention provides pharmaceutical compositions comprising at least one compound of the invention, or a pharmaceutically acceptable salt thereof, in a pharmaceutically acceptable carrier or diluent. Such compositions according to the invention may optionally further include one or more additional therapeutic agents as described herein.
- In another aspect, the present invention provides a method for treating or preventing a disease, condition, or disorder that is mediated, at least in part, by the adenosine A2a receptor and/or the adenosine A2b receptor in a subject (e.g., an animal or human) in need thereof, said method comprising administering to the subject a therapeutically effective amount of at least one compound of the invention, or a pharmaceutically acceptable salt thereof, alone or in combination with one or more additional therapeutic agents. These and other aspects and embodiments of the invention are described more fully below.
- For each of the following embodiments, any variable not explicitly defined in the embodiment is as defined in Formula (I). In each of the embodiments described herein, each variable is selected independently of the other unless otherwise noted.
- In one embodiment, the compounds of the invention have the structural Formula (I):
- or a pharmaceutically acceptable salt thereof, wherein:
- R1 is selected from F, Cl, (C1-C6)alkyl, and O(C1-C6)alkyl;
- R2 is selected from H, F, Cl, (C1-C6)alkyl, and O(C1-C6)alkyl;
- ring A is a moiety selected from:
- R3 is selected from pyrazolyl, triazolyl, and pyridinyl, wherein said pyrazolyl and said triazolyl, are substituted with 1 or 2 R3A groups, and wherein said pyridinyl is substituted with 1, 2, or 3 R3A groups, wherein:
- each R3A is independently selected from (C1-C6)alkyl, O(C1-C6)alkyl, (C1-C6)alkyl-OH, (C1-C6)haloalkyl, O(C1-C6)haloalkyl, oxo, (C1-C4)alkylC(O)(C1-C3)alkyl, (C1-C4)alkylCH(OH)(C1-C3)alkyl, (C1-C4)alkylS(O)2(C1-C3)alkyl, —(CH2)n(C3-C7)cycloalkyl, and —(CH2)n4-7 membered monocyclic heterocycloalkyl comprising 1 or 2 ring heteroatoms selected from oxygen and nitrogen, wherein said (C3-C7)cycloalkyl, and said 4-7 membered monocyclic heterocycloalkyl are each unsubstituted or substituted with 1, 2, or 3 groups independently selected from F, Cl, OH, (C1-C6)alkyl, and (C1-C6)haloalkyl;
- n is 0, 1, or 2;
- RA1 is selected from H, and (C1-C4)alkyl;
- RA2 is selected from H, F, and (C1-C4)alkyl;
- RA3 is selected from H, F, and (C1-C4)alkyl;
- RA4 is selected from H and OH; and
- RA5 is selected from H, F, and (C1-C4)alkyl.
- In another embodiment, the compounds of the invention have the structural Formula (I.1):
- or a pharmaceutically acceptable salt thereof, wherein ring A, R1, and R2 are as defined in Formula (I).
- In another embodiment, the compounds of the invention have the structural Formula (I.2):
- or a pharmaceutically acceptable salt thereof, wherein ring A, R1, and R2 are as defined in Formula (I).
- In another embodiment, in each of Formulas (I), (I.1), and (I.2):
- R1 is selected from F, Cl, and OCH3;
- R2 is selected from H, F, Cl, CH3, and OCH3.
- In another embodiment, in each of Formulas (I), (I.1), and (I.2):
- R1 is F; and
- R2 is selected from H, F, Cl, CH3, and OCH3.
- In another embodiment, in each of Formulas (I), (I.1), and (I.2):
- R1 is Cl; and
- R2 is selected from H, F, Cl, CH3, and OCH3.
- In another embodiment, in each of Formulas (I), (I.1), and (I.2):
- R1 is F; and
- R2 is OCH3.
- In another embodiment, in each of Formulas (I), (I.1), and (I.2):
- R1 is F; and
- R2 is F.
- In another embodiment, in each of Formulas (I), (I.1), and (I.2):
- R1 is F; and
- R2 is H.
- In another embodiment, in each of Formulas (I), (I.1), and (I.2):
- ring A is a moiety selected from:
- wherein R3, RA1, RA2, RA3, and RA5 are as defined in Formula (I); and wherein R1 and R2 are as defined in Formula (I) or as defined in any of the alternative embodiments of R1 and R2 described above.
- In another embodiment, in each of Formulas (I), (I.1), and (I.2):
- ring A is a moiety selected from:
- wherein:
- R3 is selected from
- wherein:
- each R3A is as defined in Formula (I);
- each RAa is independently selected from (C1-C4)alkyl, O(C1-C4)alkyl, (C1-C4)haloalkyl, and O(C1-C4)haloalkyl;
- RA1, RA2, RA3, and RA5 are as defined in Formula (I); and
- R1 and R2 are as defined in Formula (I) or as defined in any of the alternative embodiments of R1 and R2 described above.
- In another embodiment, in each of Formulas (I), (I.1), and (I.2):
- ring A is a moiety selected from:
- wherein:
- R3 is selected from
- wherein:
-
- each R3A is a moiety selected from:
- each R3Aa is independently selected from (C1-C4)alkyl, O(C1-C4)alkyl, (C1-C4)haloalkyl, and O(C1-C4)haloalkyl;
- RA1, RA2, RA3, and RA5 are as defined in Formula (I); and
- R1 and R2 are as defined in Formula (I) or as defined in any of the alternative embodiments of R1 and R2 described above.
- In an alternative of the immediately preceding embodiment:
- RA1 is selected from H, CH3, and CH2CH3;
- RA2 is selected from H, F, CH3, and CH2CH3;
- RA3 is selected from H and F; and
- RA5 is H.
- In another alternative of the immediately preceding embodiment:
- RA1 is selected from H and CH3;
- RA2 is H;
- RA3 is H; and
- RA5 is H.
- In another alternative of the immediately preceding embodiment:
- RA1 is H;
- RA2 is H;
- RA3 is H; and
- RA5 is H.
- In another embodiment, in each of Formulas (I), (I.1), and (I.2):
- ring A is the moiety:
- wherein R3 and RA3 are as defined in Formula (I); and wherein R1 and R2 are as defined in Formula (I) or as defined in any of the alternative embodiments of R1 and R2 described above.
- In another embodiment, in each of Formulas (I), (I.1), and (I.2):
- ring A is the moiety:
- wherein:
- R3 is selected from
- wherein:
-
- each R3A is as defined in Formula (I);
- each R3Aa is independently selected from (C1-C4)alkyl, O(C1-C4)alkyl, (C1-C4)haloalkyl, and O(C1-C4)haloalkyl;
- RA3 is as defined in Formula (I); and
- R1 and R2 are as defined in Formula (I) or as defined in any of the alternative embodiments of R1 and R2 described above.
- In another embodiment, in each of Formulas (I), (I.1), and (I.2):
- ring A is the moiety:
- wherein:
- R3 is selected from
- wherein:
- each R3A is a moiety selected from:
- each R3Aa is independently selected from (C1-C4)alkyl, O(C1-C4)alkyl, (C1-C4)haloalkyl, and O(C1-C4)haloalkyl;
- RA3 is as defined in Formula (I); and
- R1 and R2 are as defined in Formula (I) or as defined in any of the alternative embodiments of R1 and R2 described above.
- In an alternative of the immediately preceding embodiment:
- RA3 is selected from H and F.
- In another alternative of the immediately preceding embodiment:
- RA3 is H.
- In another embodiment, in each of Formulas (I), (I.1), and (I.2):
- ring A is the moiety:
- wherein R3 is as defined in Formula (I); and wherein R1 and R2 are as defined in Formula (I) or as defined in any of the alternative embodiments of R1 and R2 described above.
- In another embodiment, in each of Formulas (I), (I.1), and (I.2):
- ring A is the moiety:
- wherein:
- R3 is selected from
- wherein:
- each R3A is as defined in Formula (I);
- each R3Aa is independently selected from (C1-C4)alkyl, O(C1-C4)alkyl, (C1-C4)haloalkyl, and O(C1-C4)haloalkyl; and
- R1 and R2 are as defined in Formula (I) or as defined in any of the alternative embodiments of R1 and R2 described above.
- In another embodiment, in each of Formulas (I), (I.1), and (I.2):
- ring A is the moiety:
- wherein:
- R3 is selected from
- wherein:
- each R3A is a moiety selected from:
- each R3Aa is independently selected from (C1-C4)alkyl, O(C1-C4)alkyl, (C1-C4)haloalkyl, and O(C1-C4)haloalkyl; and
- R1 and R2 are as defined in Formula (I) or as defined in any of the alternative embodiments of R1 and R2 described above.
- In another embodiment, in each of Formulas (I), (I.1), and (I.2):
- ring A is the moiety:
- wherein R3 is as defined in Formula (I); and wherein R1 and R2 are as defined in Formula (I) or as defined in any of the alternative embodiments of R1 and R2 described above.
- In another embodiment, in each of Formulas (I), (I.1), and (I.2):
- ring A is the moiety:
- wherein:
- R3 is selected from
- wherein:
- each R3A is as defined in Formula (I);
- each R3Aa is independently selected from (C1-C4)alkyl, O(C1-C4)alkyl, (C1-C4)haloalkyl, and O(C1-C4)haloalkyl; and
- R1 and R2 are as defined in Formula (I) or as defined in any of the alternative embodiments of R1 and R2 described above.
- In another embodiment, in each of Formulas (I), (I.1), and (I.2):
- ring A is the moiety:
- wherein:
- R3 is selected from
- wherein:
- each R3A is a moiety selected from:
- each R3Aa is independently selected from (C1-C4)alkyl, O(C1-C4)alkyl, (C1-C4)haloalkyl, and O(C1-C4)haloalkyl; and
- R1 and R2 are as defined in Formula (I) or as defined in any of the alternative embodiments of R1 and R2 described above.
- In another embodiment, in each of Formulas (I), (I.1), and (I.2):
- ring A is the moiety:
- wherein R3, RA1, RA2, and RA3 are as defined in Formula (I); and wherein R1 and R2 are as defined in Formula (I) or as defined in any of the alternative embodiments of R1 and R2 described above.
- In another embodiment, in each of Formulas (I), (I.1), and (I.2):
- ring A is the moiety:
- wherein:
- R3 is selected from
- wherein:
- each R3A is as defined in Formula (I);
- each R3Aa is independently selected from (C1-C4)alkyl, O(C1-C4)alkyl, (C1-C4)haloalkyl, and O(C1-C4)haloalkyl;
- RA1, RA2, and RA3 are as defined in Formula (I); and
- R1 and R2 are as defined in Formula (I) or as defined in any of the alternative embodiments of R1 and R2 described above.
- In another embodiment, in each of Formulas (I), (I.1), and (I.2):
- ring A is the moiety:
- wherein:
- R3 is selected from
- wherein:
- each R3A is a moiety selected from:
- each R3Aa is independently selected from (C1-C4)alkyl, O(C1-C4)alkyl, (C1-C4)haloalkyl, and O(C1-C4)haloalkyl;
- RA1, RA2, and RA3 are as defined in Formula (I); and
- R1 and R2 are as defined in Formula (I) or as defined in any of the alternative embodiments of R1 and R2 described above.
- In an alternative of the immediately preceding embodiment:
- RA1 is selected from H, CH3, and CH2CH3;
- RA2 is selected from H, F, CH3, and CH2CH3; and
- RA3 is selected from H and F.
- In another alternative of the immediately preceding embodiment:
- RA1 is selected from H and CH3;
- RA2 is H; and
- RA3 is H.
- In another alternative of the immediately preceding embodiment:
- RA1 is H;
- RA2 is H; and
- RA3 is H.
- In another embodiment, in each of Formulas (I), (I.1), and (I.2):
- ring A is the moiety:
- wherein R3, RA1, RA2, and RA3 are as defined in Formula (I); and
- wherein R1 and R2 are as defined in Formula (I) or as defined in any of the alternative embodiments of R1 and R2 described above.
- In another embodiment, in each of Formulas (I), (I.1), and (I.2):
- ring A is the moiety:
- wherein:
- R3 is selected from
- wherein:
-
- each R3A is as defined in Formula (I);
- each R3Aa is independently selected from (C1-C4)alkyl, O(C1-C4)alkyl, (C1-C4)haloalkyl, and O(C1-C4)haloalkyl;
- RA1, RA2, and RA3 are as defined in Formula (I); and
- R1 and R2 are as defined in Formula (I) or as defined in any of the alternative embodiments of R1 and R2 described above.
- In another embodiment, in each of Formulas (I), (I.1), and (I.2):
- ring A is the moiety:
- wherein:
- R3 is selected from
- wherein:
- each R3A is a moiety selected from:
- each R3Aa is independently selected from (C1-C4)alkyl, O(C1-C4)alkyl, (C1-C4)haloalkyl, and O(C1-C4)haloalkyl;
- RA1, RA2, and RA3 are as defined in Formula (I); and
- R1 and R2 are as defined in Formula (I) or as defined in any of the alternative embodiments of R1 and R2 described above.
- In an alternative of the immediately preceding embodiment:
- RA1 is selected from H, CH3, and CH2CH3;
- RA2 is selected from H, F, CH3, and CH2CH3; and
- RA3 is selected from H and F.
- In another alternative of the immediately preceding embodiment:
- RA1 is selected from H and CH3;
- RA2 is H; and
- RA3 is H.
- In another alternative of the immediately preceding embodiment:
- RA1 is H;
- RA2 is H; and
- RA3 is H.
- In another embodiment, in each of Formulas (I), (I.1), and (I.2):
- ring A is the moiety:
- wherein R3, RA1, RA2, RA3 and RA4 are as defined in Formula (I); and
- wherein R1 and R2 are as defined in Formula (I) or as defined in any of the alternative embodiments of R1 and R2 described above.
- In another embodiment, in each of Formulas (I), (I.1), and (I.2):
- ring A is the moiety:
- wherein:
- R3 is selected from
- wherein:
- each R3A is as defined in Formula (I);
- each R3Aa is independently selected from (C1-C4)alkyl, O(C1-C4)alkyl, (C1-C4)haloalkyl, and O(C1-C4)halo alkyl;
- RA1, RA2, RA3 and RA4 re as defined in Formula (I); and
- R1 and R2 are as defined in Formula (I) or as defined in any of the alternative embodiments of R1 and R2 described above.
- In another embodiment, in each of Formulas (I), (I.1), and (I.2):
- ring A is the moiety:
- wherein:
- R3 is selected from
- wherein:
- each R3A is a moiety selected from:
- each RAa is independently selected from (C1-C4)alkyl, O(C1-C4)alkyl, (C1-C4)haloalkyl, and O(C1-C4)haloalkyl;
- RA1; RA2; RA3 and RA4 re as defined in Formula (I); and
- R1 and R2 are as defined in Formula (I) or as defined in any of the alternative embodiments of R1 and R2 described above.
- In an alternative of the immediately preceding embodiment:
- RA1 is selected from H, CH3, and CH2CH3;
- RA2 is selected from H, F, CH3, and CH2CH3;
- RA3 is selected from H and F; and
- RA4 is selected from H and OH.
- In an alternative of the immediately preceding embodiment:
- RA1 is H;
- RA2 is H;
- RA3 is H; and
- RA4 is selected from H and OH.
- In another embodiment, the compounds of the invention comprise those compounds identified herein as examples in the tables below, and pharmaceutically acceptable salts thereof.
- In another aspect, the present invention provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a compound of the invention or a pharmaceutically acceptable salt thereof. Such compositions according to the invention may optionally further include one or more additional therapeutic agents as described herein.
- In another aspect, the present invention provides a method for the manufacture of a medicament or a composition which may be useful for treating diseases, conditions, or disorders that are mediated, at least in part, by the adenosine A2a receptor and/or the adenosine A2b receptor, comprising combining a compound of the invention with one or more pharmaceutically acceptable carriers.
- In another aspect, the present invention provides a method for treating or preventing a disease, condition, or disorder that is mediated, at least in part, by the adenosine A2a receptor and/or the adenosine A2b receptor in a subject (e.g., an animal or human) in need thereof, said method comprising administering to the subject in need thereof a therapeutically effective amount of at least one compound of the invention, or a pharmaceutically acceptable salt thereof, alone or in combination with one or more additional therapeutic agents. Specific non-limiting examples of such diseases, conditions, and disorders are described herein.
- In some embodiments, the disease, condition or disorder is a cancer. Any cancer for which a PD-1 antagonist and/or an A2a and/or A2b inhibitor are thought to be useful by those of ordinary skill in the art are contemplated as cancers treatable by this embodiment, either as a monotherapy or in combination with other therapeutic agents discussed below. Cancers that express high levels of A2a receptors or A2b receptors are among those cancers contemplated as treatable by the compounds of the invention. Examples of cancers that express high levels of A2a and/or A2b receptors may be discerned by those of ordinary skill in the art by reference to the Cancer Genome Atlas (TCGA) database. Non-limiting examples of cancers that express high levels of A2a receptors include cancers of the kidney, breast, lung, and liver. Non-limiting examples of cancers that express high levels of the A2b receptor include lung, colorectal, head & neck cancer, and cervical cancer.
- Thus, one embodiment provides a method of treating cancer comprising administering an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, to a subject in need of such treatment, wherein said cancer is a cancer that expresses a high level of A2a receptor. A related embodiment provides a method of treating cancer comprising administering an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, to a subject in need of such treatment, wherein said cancer is selected from kidney (or renal) cancer, breast cancer, lung cancer, and liver cancer.
- Another embodiment provides a method of treating cancer comprising administering an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, to a subject in need of such treatment, wherein said cancer is a cancer that expresses a high level of A2b receptor. A related embodiment provides a method of treating cancer comprising administering an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, to a subject in need of such treatment, wherein said cancer is selected from lung cancer, colorectal cancer, head & neck cancer, and cervical cancer.
- Additional non-limiting examples of cancers which may be treatable by administration of a compound of the invention (alone or in combination with one or more additional agents described below) include cancers of the prostate (including but not limited to metastatic castration resistant prostate cancer), colon, rectum, pancreas, cervix, stomach, endometrium, brain, liver, bladder, ovary, testis, head, neck, skin (including melanoma and basal carcinoma), mesothelial lining, white blood cell (including lymphoma and leukemia) esophagus, breast, muscle, connective tissue, lung (including but not limited to small cell lung cancer, non-small cell lung cancer, and lung adenocarcinoma), adrenal gland, thyroid, kidney, or bone. Additional cancers treatable by a compound of the invention include glioblastoma, mesothelioma, renal cell carcinoma, gastric carcinoma, sarcoma, choriocarcinoma, cutaneous basocellular carcinoma, and testicular seminoma, and Kaposi's sarcoma.
- In other embodiments, the disease, condition or disorder is a central nervous system or a neurological disorder. Non-limiting examples of such diseases, conditions or disorders include movement disorders such as tremors, bradykinesias, gait disorders, dystonias, dyskinesias, tardive dyskinesias, other extrapyramidal syndromes, Parkinson's disease, and disorders associated with Parkinson's disease. The compounds of the invention also have the potential, or are believed to have the potential, for use in preventing or reducing the effect of drugs that cause or worsen such movement disorders.
- In other embodiments, the disease, condition or disorder is an infective disorder. Non-limiting examples of such diseases, conditions or disorders include an acute or chronic viral infection, a bacterial infection, a fungal infection, or a parasitic infection. In one embodiment, the viral infection is human immunodeficiency virus. In another embodiment, the viral infection is cytomegalovirus.
- In other embodiments, the disease, condition or disorder is an immune-related disease, condition or disorder. Non-limiting examples of immune-related diseases, conditions, or disorders include multiple sclerosis and bacterial infections. (See, e.g., Safarzadeh, E. et al., Inflamm Res 2016 65(7):511-20; and Antonioli, L., et al., Immunol Lett S0165-2478(18)30172-X 2018).
- Other diseases, conditions, and disorders that have the potential to be treated or prevented, in whole or in part, by the inhibition of the A2a and/or A2b adenosine receptor(s) are also candidate indications for the compounds of the invention and salts thereof. Non-limiting examples of other diseases, conditions or disorders in which a compound of the invention, or a pharmaceutically acceptable salt thereof, may be useful include the treatment of hypersensitivity reaction to a tumor antigen and the amelioration of one or more complications related to bone marrow transplant or to a peripheral blood stem cell transplant. Thus, in another embodiment, the present invention provides a method for treating a subject receiving a bone marrow transplant or a peripheral blood stem cell transplant by administering to said subject a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, sufficient to increase the delayed-type hypersensitivity reaction to tumor antigen, to delay the time-to-relapse of post-transplant malignancy, to increase relapse-free survival time post-transplant, and/or to increase long-term post-transplant survival.
- In another aspect, the present invention provides methods for the use of a compound of the invention, or a pharmaceutically acceptable salt thereof, (or a pharmaceutically acceptable composition comprising a compound of the invention or pharmaceutically acceptable salt thereof) in combination with one or more additional agents. Such additional agents may have some adenosine A2a and/or A2b receptor activity, or, alternatively, they may function through distinct mechanisms of action. The compounds of the invention may be used in combination with one or more other drugs in the treatment, prevention, suppression or amelioration of diseases or conditions for which the compounds of the invention or the other drugs described herein may have utility, where the combination of the drugs together are safer or more effective than either drug alone. The combination therapy may have an additive or synergistic effect. Such other drug(s) may be administered in an amount commonly used therefore, contemporaneously or sequentially with a compound of the invention or a pharmaceutically acceptable salt thereof. When a compound of the invention is used contemporaneously with one or more other drugs, the pharmaceutical composition may in specific embodiments contain such other drugs and the compound of the invention or its pharmaceutically acceptable salt in separate doses or in unit dosage form. However, the combination therapy may also include therapies in which the compound of the invention or its pharmaceutically acceptable salt and one or more other drugs are administered sequentially, on different or overlapping schedules. It is also contemplated that when used in combination with one or more other active ingredients, the compounds of the invention and the other active ingredients may be used in lower doses than when each is used singly. Accordingly, the pharmaceutical compositions comprising the compounds of the invention include those that contain one or more other active ingredients, in addition to a compound of the invention or a pharmaceutically acceptable salt thereof.
- The weight ratio of the compound of the present invention to the second active ingredient may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used. Thus, for example, when a compound of the invention is used in combination with another agent, the weight ratio of the compound of the present invention to the other agent may generally range from about 1000:1 to about 1:1000, in particular embodiments from about 200:1 to about 1:200. Combinations of a compound of the present invention and other active ingredients will generally also be within the aforementioned range, but in each case, an effective dose of each active ingredient should generally be used.
- Given the immunosuppressive role of adenosine, the administration of an A2a receptor antagonist, an A2b receptor antagonist, and/or an A2a/A2b receptor dual antagonist according to the invention may enhance the efficacy of immunotherapies such as PD-1 antagonists. Thus, in one embodiment, the additional therapeutic agent comprises an anti-PD-1 antibody. In another embodiment, the additional therapeutic agent is an anti-PD-L1 antibody.
- As noted above, PD-1 is recognized as having an important role in immune regulation and the maintenance of peripheral tolerance. PD-1 is moderately expressed on naive T-cells, B-cells and NKT-cells and up-regulated by T-cell and B-cell receptor signaling on lymphocytes, monocytes and myeloid cells (Sharpe et al., Nature Immunology (2007); 8:239-245).
- Two known ligands for PD-1, PD-L1 (B7-H1) and PD-L2 (B7-DC) are expressed in human cancers arising in various tissues. In large sample sets of, for example, ovarian, renal, colorectal, pancreatic, and liver cancers, and in melanoma, it was shown that PD-L1 expression correlated with poor prognosis and reduced overall survival irrespective of subsequent treatment. (Dong et al., Nat Med. 8(8):793-800 (2002); Yang et al., Invest Ophthamol Vis Sci. 49: 2518-2525 (2008); Ghebeh et al., Neoplasia 8:190-198 (2006); Hamanishi et al., Proc. Natl. Acad. Sci. USA 104: 3360-3365 (2007); Thompson et al., Cancer 5: 206-211 (2006); Nomi et al., Clin. Cancer Research 13:2151-2157 (2007); Ohigashi et al., Clin. Cancer Research 11: 2947-2953; Inman et al., Cancer 109: 1499-1505 (2007); Shimauchi et al., Int. J. Cancer 121:2585-2590 (2007); Gao et al., Clin. Cancer Research 15: 971-979 (2009); Nakanishi J., Cancer Immunol Immunother. 56: 1173-1182 (2007); and Hino et al., Cancer 00: 1-9 (2010)).
- Similarly, PD-1 expression on tumor infiltrating lymphocytes was found to mark dysfunctional T-cells in breast cancer and melanoma (Ghebeh et al., BMC Cancer. 2008 8:5714-15 (2008); and Ahmadzadeh et al., Blood 114: 1537-1544 (2009)) and to correlate with poor prognosis in renal cancer (Thompson et al., Clinical Cancer Research 15: 1757-1761(2007)). Thus, it has been proposed that PD-L1 expressing tumor cells interact with PD-1 expressing T-cells to attenuate T-cell activation and to evade immune surveillance, thereby contributing to an impaired immune response against the tumor.
- Immune checkpoint therapies targeting the PD-1 axis have resulted in groundbreaking improvements in clinical response in multiple human cancers (Brahmer, et al., N Engl J Med 2012, 366: 2455-65; Garon et al., N Engl J Med 2015, 372: 2018-28; Hamid et al., N Engl J Med 2013, 369: 134-44; Robert et al., Lancet 2014, 384: 1109-17; Robert et al., N Engl J Med 2015, 372: 2521-32; Robert et al., N Engl J Med 2015, 372: 320-30; Topalian et al., N Engl J Med 2012, 366: 2443-54; Topalian et al., J Clin Oncol 2014, 32: 1020-30; and Wolchok et al., N Engl J Med 2013, 369: 122-33).
- “PD-1 antagonist” means any chemical compound or biological molecule that blocks binding of PD-L1 expressed on a cancer cell to PD-1 expressed on an immune cell (T-cell, B-cell or NKT cell) and preferably also blocks binding of PD-L2 expressed on a cancer cell to the immune-cell expressed PD-1. Alternative names or synonyms for PD-1 and its ligands include: PDCD1, PD1, CD279 and SLEB2 for PD-1; PDCD1L1, PDL1, B7H1, B7-4, CD274 and B7-H for PD-L1; and PDCD1L2, PDL2, B7-DC, Btdc and CD273 for PD-L2. In any of the treatment methods, medicaments and uses of the present invention in which a human individual is being treated, the PD-1 antagonist blocks binding of human PD-L1 to human PD-1, and preferably blocks binding of both human PD-L1 and PD-L2 to human PD-1. Human PD-1 amino acid sequences can be found in NCBI Locus No.: NP 005009. Human PD-L1 and PD-L2 amino acid sequences can be found in NCBI Locus No.: NP_054862 and NP_079515, respectively.
- PD-1 antagonists useful in any of the treatment methods, medicaments and uses of the present invention include a monoclonal antibody (mAb), or antigen binding fragment thereof, which specifically binds to PD-1 or PD-L1, and preferably specifically binds to human PD-1 or human PD-L1. The mAb may be a human antibody, a humanized antibody or a chimeric antibody, and may include a human constant region. In some embodiments the human constant region is selected from the group consisting of IgG1, IgG2, IgG3 and IgG4 constant regions, and in preferred embodiments, the human constant region is an IgG1 or IgG4 constant region. In some embodiments, the antigen binding fragment is selected from the group consisting of Fab, Fab′-SH, F(ab′)2, scFv and Fv fragments. Examples of PD-1 antagonists include, but are not limited to, pembrolizumab (KEYTRUDA®, Merck and Co., Inc., Kenilworth, N.J., USA). “Pembrolizumab” (formerly known as MK-3475, SCH 900475 and lambrolizumab and sometimes referred to as “pembro”) is a humanized IgG4 mAb with the structure described in WHO Drug Information, Vol. 27, No. 2, pages 161-162 (2013). Additional examples of PD-1 antagonists include nivolumab (OPDIVO®, Bristol-Myers Squibb Company, Princeton, N.J., USA), atezolizumab (MPDL3280A; TECENTRIQ®, Genentech, San Francisco, Calif., USA), durvalumab (IMFINZI®, Astra Zeneca Pharmaceuticals, LP, Wilmington, Del., and avelumab (BAVENCIO®, Merck KGaA, Darmstadt, Germany and Pfizer, Inc., New York, N.Y.).
- Examples of monoclonal antibodies (mAbs) that bind to human PD-1, and useful in the treatment methods, medicaments and uses of the present invention, are described in U.S. Pat. Nos. 7,488,802, 7,521,051, 8,008,449, 8,354,509, 8,168,757, WO2004/004771, WO2004/072286, WO2004/056875, and US2011/0271358.
- Examples of mAbs that bind to human PD-L1, and useful in the treatment methods, medicaments and uses of the present invention, are described in WO2013/019906, WO2010/077634 A1 and U.S. Pat. No. 8,383,796. Specific anti-human PD-L1 mAbs useful as the PD-1 antagonist in the treatment method, medicaments and uses of the present invention include MPDL3280A, BMS-936559, MEDI4736, MSB0010718C and an antibody which comprises the heavy chain and light chain variable regions of SEQ ID NO:24 and SEQ ID NO:21, respectively, of WO2013/019906.
- Other PD-1 antagonists useful in any of the treatment methods, medicaments and uses of the present invention include an immunoadhesin that specifically binds to PD-1 or PD-L1, and preferably specifically binds to human PD-1 or human PD-L1, e.g., a fusion protein containing the extracellular or PD-1 binding portion of PD-L1 or PD-L2 fused to a constant region such as an Fc region of an immunoglobulin molecule. Examples of immunoadhesin molecules that specifically bind to PD-1 are described in WO2010/027827 and WO2011/066342. Specific fusion proteins useful as the PD-1 antagonist in the treatment methods, medicaments and uses of the present invention include AMP-224 (also known as B7-DCIg), which is a PD-L2-FC fusion protein that binds to human PD-1.
- Thus, one embodiment provides for a method of treating cancer comprising administering an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, in combination with a PD-1 antagonist to a subject in need thereof. In such embodiments, the compounds of the invention, or a pharmaceutically acceptable salt thereof, and PD-1 antagonist are administered concurrently or sequentially.
- Specific non-limiting examples of such cancers in accordance with this embodiment include melanoma (including unresectable or metastatic melanoma), head & neck cancer (including recurrent or metastatic head and neck squamous cell cancer (HNSCC)), classical Hodgkin lymphoma (cHL), urothelial carcinoma, gastric cancer, cervical cancer, primary mediastinal large-B-cell lymphoma, microsatellite instability-high (MSI-H) cancer, non-small cell lung cancer, hepatocellular carcinoma, clear cell kidney cancer, colorectal cancer, breast cancer, squamous cell lung cancer, basal carcinoma, sarcoma, bladder cancer, endometrial cancer, pancreatic cancer, liver cancer, gastrointestinal cancer, multiple myeloma, renal cancer, mesothelioma, ovarian cancer, anal cancer, biliary tract cancer, esophageal cancer, and salivary cancer.
- In one embodiment, there is provided a method of treating cancer comprising administering an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, to a person in need thereof, in combination with a PD-1 antagonist, wherein said cancer is selected from unresectable or metastatic melanoma, recurrent or metastatic head and neck squamous cell cancer (HNSCC), classical Hodgkin lymphoma (cHL), urothelial carcinoma, gastric cancer, cervical cancer, primary mediastinal large-B-cell lymphoma, microsatellite instability-high (MSI-H) cancer, non-small cell lung cancer, and hepatocellular carcinoma. In one such embodiment, the agent is a PD-1 antagonist. In one such embodiment, the agent is pembrolizumab. In another such embodiment, the agent is nivolumab. In another such embodiment, the agent is atezolizumab.
- Pembrolizumab is approved by the U.S. FDA for the treatment of patients with unresectable or metastatic melanoma and for the treatment of certain patients with recurrent or metastatic head and neck squamous cell cancer (HNSCC), classical Hodgkin lymphoma (cHL), urothelial carcinoma, gastric cancer, cervical cancer, primary mediastinal large-B-cell lymphoma, microsatellite instability-high (MSI-H) cancer, non-small cell lung cancer, and hepatocellular carcinoma, as described in the Prescribing Information for KEYTRUDA™ (Merck & Co., Inc., Whitehouse Station, N.J. USA; initial U.S. approval 2014, updated November 2018). In another embodiment, there is provided a method of treating cancer comprising administering an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, to a person in need thereof, in combination with pembrolizumab, wherein said cancer is selected from unresectable or metastatic melanoma, recurrent or metastatic head and neck squamous cell cancer (HNSCC), classical Hodgkin lymphoma (cHL), urothelial carcinoma, gastric cancer, cervical cancer, primary mediastinal large-B-cell lymphoma, microsatellite instability-high (MSI-H) cancer, non-small cell lung cancer, and hepatocellular carcinoma.
- In another embodiment, there is provided a method of treating cancer comprising administering an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, to a person in need thereof, in combination with a PD-1 antagonist, wherein said cancer is selected from melanoma, non-small cell lung cancer, head and neck squamous cell cancer (HNSCC), Hodgkin lymphoma, primary mediastinal large B-cell lymphoma, urothelial carcinoma, micro satellite instability-high cancer, gastric cancer, Merkel cell carcinoma, hepatocellular carcinoma, esophageal cancer and cervical cancer. In one such embodiment, the agent is a PD-1 antagonist. In one such embodiment, the agent is pembrolizumab. In another such embodiment, the agent is nivolumab. In another such embodiment, the agent is atezolizumab. In another such embodiment, the agent is durvalumab. In another such embodiment, the agent is avelumab.
- In another embodiment, there is provided a method of treating cancer comprising administering an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, to a person in need thereof, in combination with a PD-1 antagonist, wherein said cancer is selected from melanoma, non-small cell lung cancer, small cell lung cancer, head and neck cancer, bladder cancer, breast cancer, gastrointestinal cancer, multiple myeloma, hepatocellular cancer, lymphoma, renal cancer, mesothelioma, ovarian cancer, esophageal cancer, anal cancer, biliary tract cancer, colorectal cancer, cervical cancer, thyroid cancer, and salivary cancer. In one such embodiment, the agent is a PD-1 antagonist. In one such embodiment, the agent is pembrolizumab. In another such embodiment, the agent is nivolumab. In another such embodiment, the agent is atezolizumab. In another such embodiment, the agent is durvalumab. In another such embodiment, the agent is avelumab.
- In one embodiment, there is provided a method of treating unresectable or metastatic melanoma comprising administering an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, to a person in need thereof, in combination with a PD-1 antagonist. In one such embodiment, the agent is pembrolizumab. In another such embodiment, the agent is nivolumab. In another such embodiment, the agent is atezolizumab.
- In one embodiment, there is provided a method of treating recurrent or metastatic head and neck squamous cell cancer (HNSCC) comprising administering an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, to a person in need thereof, in combination with a PD-1 antagonist. In one such embodiment, the agent is pembrolizumab. In another such embodiment, the agent is nivolumab. In another such embodiment, the agent is atezolizumab.
- In one embodiment, there is provided a method of treating classical Hodgkin lymphoma (cHL) comprising administering an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, to a person in need thereof, in combination with a PD-1 antagonist. In one such embodiment, the agent is pembrolizumab. In another such embodiment, the agent is nivolumab. In another such embodiment, the agent is atezolizumab.
- In one embodiment, there is provided a method of treating urothelial carcinoma comprising administering an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, to a person in need thereof, in combination with a PD-1 antagonist. In one such embodiment, the agent is pembrolizumab. In another such embodiment, the agent is nivolumab. In another such embodiment, the agent is atezolizumab.
- In one embodiment, there is provided a method of treating gastric cancer comprising administering an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, to a person in need thereof, in combination with a PD-1 antagonist. In one such embodiment, the agent is pembrolizumab. In another such embodiment, the agent is nivolumab. In another such embodiment, the agent is atezolizumab.
- In one embodiment, there is provided a method of treating cervical cancer comprising administering an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, to a person in need thereof, in combination with a PD-1 antagonist. In one such embodiment, the agent is pembrolizumab. In another such embodiment, the agent is nivolumab. In another such embodiment, the agent is atezolizumab.
- In one embodiment, there is provided a method of treating primary mediastinal large-B-cell lymphoma comprising administering an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, to a person in need thereof, in combination with a PD-1 antagonist. In one such embodiment, the agent is pembrolizumab. In another such embodiment, the agent is nivolumab. In another such embodiment, the agent is atezolizumab.
- In one embodiment, there is provided a method of treating microsatellite instability-high (MSI-H) cancer comprising administering an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, to a person in need thereof, in combination with a PD-1 antagonist. In one such embodiment, the agent is pembrolizumab. In another such embodiment, the agent is nivolumab. In another such embodiment, the agent is atezolizumab.
- In one embodiment, there is provided a method of treating non-small cell lung cancer comprising administering an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, to a person in need thereof, in combination with a PD-1 antagonist. In one such embodiment, the agent is pembrolizumab. In another such embodiment, the agent is nivolumab. In another such embodiment, the agent is atezolizumab.
- In one embodiment, there is provided a method of treating hepatocellular carcinoma comprising administering an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, to a person in need thereof, in combination with a PD-1 antagonist. In one such embodiment, the agent is pembrolizumab. In another such embodiment, the agent is nivolumab. In another such embodiment, the agent is atezolizumab.
- In another embodiment, the additional therapeutic agent is at least one immunomodulator other than an A2a or A2b receptor inhibitor. Non-limiting examples of immunomodulators include CD40L, B7, B7RP1, anti-CD40, anti-CD38, anti-ICOS, 4-IBB ligand, dendritic cell cancer vaccine, IL2, IL12, ELC/CCL19, SLC/CCL21, MCP-1, IL-4, IL-18, TNF, IL-15, MDC, IFN-a/-13, M-CSF, IL-3, GM-CSF, IL-13, anti-IL-10 and indolamine 2,3-dioxygenase 1 (ID01) inhibitors.
- In another embodiment, the additional therapeutic agent comprises radiation. Such radiation includes localized radiation therapy and total body radiation therapy.
- In another embodiment, the additional therapeutic agent is at least one chemotherapeutic agent. Non-limiting examples of chemotherapeutic agents contemplated for use in combination with the compounds of the invention include: pemetrexed, alkylating agents (e.g., nitrogen mustards such as chlorambucil, cyclophosphamide, isofamide, mechlorethamine, melphalan, and uracil mustard; aziridines such as thiotepa; methanesulphonate esters such as busulfan; nucleoside analogs (e.g., gemcitabine); nitroso ureas such as carmustine, lomustine, and streptozocin; topoisomerase 1 inhibitors (e.g., irinotecan); platinum complexes such as cisplatin, carboplatin and oxaliplatin; bioreductive alkylators such as mitomycin, procarbazine, dacarbazine and altretamine); anthracycline-based therapies (e.g., doxorubicin, daunorubicin, epirubicin and idarubicin); DNA strand-breakage agents (e.g., bleomycin); topoisomerase II inhibitors (e.g., amsacrine, dactinomycin, daunorubicin, idarubicin, mitoxantrone, doxorubicin, etoposide, and teniposide); DNA minor groove binding agents (e.g., plicamydin); antimetabolites (e.g., folate antagonists such as methotrexate and trimetrexate; pyrimidine antagonists such as fluorouracil, fluorodeoxyuridine, CB3717, azacitidine, cytarabine, and floxuridine; purine antagonists such as mercaptopurine, 6-thioguanine, fludarabine, pentostatin; asparginase; and ribonucleotide reductase inhibitors such as hydroxyurea); tubulin interactive agents (e.g., vincristine, estramustine, vinblastine, docetaxol, epothilone derivatives, and paclitaxel); hormonal agents (e.g., estrogens; conjugated estrogens; ethynyl estradiol; diethylstilbesterol; chlortrianisen; idenestrol; progestins such as hydroxyprogesterone caproate, medroxyprogesterone, and megestrol; and androgens such as testosterone, testosterone propionate, fluoxymesterone, and methyltestosterone); adrenal corticosteroids (e.g., prednisone, dexamethasone, methylprednisolone, and prednisolone); luteinizing hormone releasing agents or gonadotropin-releasing hormone antagonists (e.g., leuprolide acetate and goserelin acetate); and antihormonal antigens (e.g., tamoxifen, antiandrogen agents such as flutamide; and antiadrenal agents such as mitotane and aminoglutethimide).
- In another embodiment, the additional therapeutic agent is at least one signal transduction inhibitor (STI). Non-limiting examples of signal transduction inhibitors include BCR/ABL kinase inhibitors, epidermal growth factor (EGF) receptor inhibitors, HER-2/neu receptor inhibitors, and farnesyl transferase inhibitors (FTIs).
- In another embodiment, the additional therapeutic agent is at least one anti-infective agent. Non-limiting examples of anti-infective agents include cytokines, non-limiting examples of which include granulocyte-macrophage colony stimulating factor (GM-CSF) and an flt3-ligand.
- In another embodiment, the present invention provides a method for treating or preventing a viral infection (e.g., a chronic viral infection) including, but not limited to, hepatitis C virus (HCV), human papilloma virus (HPV), cytomegalovirus (CMV), Epstein-Barr virus (EBV), varicella zoster virus, coxsackievirus, and human immunodeficiency virus (HIV).
- In another embodiment, the present invention provides a method for the treatment of an infective disorder, said method comprising administering to a subject in need thereof an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, in combination with a vaccine. In some embodiments, the vaccine is an anti-viral vaccine, including, for example, an anti-HTV vaccine. Other antiviral agents contemplated for use include an anti-HIV, anti-HPV, anti HCV, anti HSV agents and the like. In other embodiments, the vaccine is effective against tuberculosis or malaria. In still other embodiments, the vaccine is a tumor vaccine (e.g., a vaccine effective against melanoma); the tumor vaccine may comprise genetically modified tumor cells or a genetically modified cell line, including genetically modified tumor cells or a genetically modified cell line that has been transfected to express granulocyte-macrophage stimulating factor (GM-CSF). In another embodiment, the vaccine includes one or more immunogenic peptides and/or dendritic cells.
- In another embodiment, the present invention provides for the treatment of an infection by administering a compound of the invention, or a pharmaceutically acceptable salt thereof, and at least one additional therapeutic agent, wherein a symptom of the infection observed after administering both the compound of the invention (or a pharmaceutically acceptable salt thereof) and the additional therapeutic agent is improved over the same symptom of infection observed after administering either alone. In some embodiments, the symptom of infection observed can be reduction in viral load, increase in CD4+ T cell count, decrease in opportunistic infections, increased survival time, eradication of chronic infection, or a combination thereof.
- As used herein, unless otherwise specified, the following terms have the following meanings.
- Unsatisfied valences in the text, schemes, examples, structural formulae, and any Tables herein are assumed to have a hydrogen atom or atoms of sufficient number to satisfy the valences.
- When a variable appears more than once in any moiety or in any compound of the invention (e.g., aryl, heterocycle, N(R)2), the selection of moieties defining that variable for each occurrence is independent of its definition at every other occurrence unless specified otherwise in the local variable definition.
- As used herein, unless otherwise specified, the term “A2a receptor antagonist” (equivalently, A2a antagonist) and/or “A2b receptor antagonist” (equivalently, A2b antagonist) means a compound exhibiting a potency (IC50) of less than about 1 μM with respect to the A2a and/or A2b receptors, respectively, when assayed in accordance with the procedures described herein. Preferred compounds exhibit at least 10-fold selectivity for antagonizing the A2a receptor and/or the A2b receptor over any other adenosine receptor (e.g., A1 or A3).
- As described herein, unless otherwise indicated, the use of a compound in treatment means that an amount of the compound, generally presented as a component of a formulation that comprises other excipients, is administered in aliquots of an amount, and at time intervals, which provides and maintains at least a therapeutic serum level of at least one pharmaceutically active form of the compound over the time interval between dose administrations.
- The phrase “at least one” used in reference to the number of components comprising a composition, for example, “at least one pharmaceutical excipient” means that one member of the specified group is present in the composition, and more than one may additionally be present. Components of a composition are typically aliquots of isolated pure material added to the composition, where the purity level of the isolated material added into the composition is the normally accepted purity level for a reagent of the type.
- Whether used in reference to a substituent on a compound or a component of a pharmaceutical composition the phrase “one or more”, means the same as “at least one”.
- “Concurrently” and “contemporaneously” both include in their meaning (1) simultaneously in time (e.g., at the same time); and (2) at different times but within the course of a common treatment schedule.
- “Consecutively” means one following the other.
- “Sequentially” refers to a series administration of therapeutic agents that awaits a period of efficacy to transpire between administering each additional agent; this is to say that after administration of one component, the next component is administered after an effective time period after the first component; the effective time period is the amount of time given for realization of a benefit from the administration of the first component.
- “Effective amount” or “therapeutically effective amount” is meant to describe the provision of an amount of at least one compound of the invention or of a composition comprising at least one compound of the invention which is effective in treating or inhibiting a disease or condition described herein, and thus produce the desired therapeutic, ameliorative, inhibitory or preventative effect. For example, in treating a cancer as described herein with one or more of the compounds of the invention optionally in combination with one or more additional agents, “effective amount” (or “therapeutically effective amount”) means, for example, providing the amount of at least one compound of the invention that results in a therapeutic response in a patient afflicted with the disease, condition, or disorder, including a response suitable to manage, alleviate, ameliorate, or treat the condition or alleviate, ameliorate, reduce, or eradicate one or more symptoms attributed to the condition and/or long-term stabilization of the condition, for example, as may be determined by the analysis of pharmacodynamic markers or clinical evaluation of patients afflicted with the condition.
- “Patient” and “subject” means an animal, such as a mammal (e.g., a human being) and is preferably a human being.
- “Prodrug” means compounds that are rapidly transformed, for example, by hydrolysis in blood, in vivo to the parent compound, e.g., conversion of a prodrug of a compound of the invention to a compound of the invention, or to a salt thereof. A thorough discussion is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference; the scope of this invention includes prodrugs of the novel compounds of this invention.
- The term “substituted” means that one or more of the moieties enumerated as substituents (or, where a list of substituents are not specifically enumerated, the substituents specified elsewhere in this application) for the particular type of substrate to which said substituent is appended, provided that such substitution does not exceed the normal valence rules for the atom in the bonding configuration presented in the substrate, and that the substitution ultimate provides a stable compound, which is to say that such substitution does not provide compounds with mutually reactive substituents located geminal or vicinal to each other; and wherein the substitution provides a compound sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture.
- Where optional substitution by a moiety is described (e.g. “optionally substituted”) the term means that if substituents are present, one or more of the enumerated (or default) moieties listed as optional substituents for the specified substrate can be present on the substrate in a bonding position normally occupied by the default substituent, for example, a hydrogen atom on an alkyl chain can be substituted by one of the optional substituents, in accordance with the definition of “substituted” presented herein.
- “Alkyl” means an aliphatic hydrocarbon group, which may be straight or branched, comprising 1 to 10 carbon atoms. “(C1-C6)alkyl” means an aliphatic hydrocarbon group, which may be straight or branched, comprising 1 to 6 carbon atoms. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkyl chain. Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, i-butyl, and t-butyl.
- “Haloalkyl” means an alkyl as defined above wherein one or more hydrogen atoms on the alkyl (up to and including each available hydrogen group) is replaced by a halogen atom. As appreciated by those of skill in the art, “halo” or “halogen” as used herein is intended to include chloro (Cl), fluoro (F), bromo (Br) and iodo (I). Chloro (Cl) and fluoro(F) halogens are generally preferred.
- “Aryl” means an aromatic monocyclic or multicyclic ring system comprising 6 to 14 carbon atoms, preferably 6 to 10 carbon atoms. The aryl group can be optionally substituted with one or more “ring system substituents” which may be the same or different, and are as defined herein. Non-limiting examples of suitable aryl groups include phenyl and naphthyl. “Monocyclic aryl” means phenyl.
- “Heteroaryl” means an aromatic monocyclic or multicyclic ring system comprising 5 to 14 ring atoms, preferably 5 to 10 ring atoms, in which one or more of the ring atoms is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination. Preferred heteroaryls contain 5 to 6 ring atoms. The “heteroaryl” can be optionally substituted by one or more substituents, which may be the same or different, as defined herein. The prefix aza, oxa or thia before the heteroaryl root name means that at least a nitrogen, oxygen or sulfur atom respectively, is present as a ring atom. A nitrogen atom of a heteroaryl can be optionally oxidized to the corresponding N-oxide. “Heteroaryl” may also include a heteroaryl as defined above fused to an aryl as defined above. Non-limiting examples of suitable heteroaryls include pyridyl, pyrazinyl, furanyl, thienyl (which alternatively may be referred to as thiophenyl), pyrimidinyl, pyridone (including N-substituted pyridones), isoxazolyl, isothiazolyl, oxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl, 1,2,4-thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl, oxindolyl, imidazo[1,2-a]pyridinyl, imidazo[2,1-b]thiazolyl, benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl, imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl, pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl, 1,2,4-triazinyl, benzothiazolyl and the like. The term “heteroaryl” also refers to partially saturated heteroaryl moieties such as, for example, tetrahydroisoquinolyl, tetrahydroquinolyl and the like. The term “monocyclic heteroaryl” refers to monocyclic versions of heteroaryl as described above and includes 4- to 7-membered monocyclic heteroaryl groups comprising from 1 to 4 ring heteroatoms, said ring heteroatoms being independently selected from the group consisting of N, O, and S, and oxides thereof. The point of attachment to the parent moiety is to any available ring carbon or ring heteroatom. Non-limiting examples of monocyclic heteroaryl moieties include pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, pyridazinyl, pyridinyl, thiazolyl, isothiazolyl, oxazolyl, oxadiazolyl, isoxazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl, thiadiazolyl (e.g., 1,2,4-thiadiazolyl), imidazolyl, and triazinyl (e.g., 1,2,4-triazinyl), and oxides thereof.
- “Cycloalkyl” means a non-aromatic fully saturated monocyclic or multicyclic ring system comprising 3 to 10 carbon atoms, preferably 3 to 6 carbon atoms. The cycloalkyl can be optionally substituted with one or more substituents, which may be the same or different, as described herein. Monocyclic cycloalkyl refers to monocyclic versions of the cycloalkyl moieties described herein. Non-limiting examples of suitable monocyclic cycloalkyls include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. Non-limiting examples of multicyclic cycloalkyls include [1.1.1]-bicyclopentane, 1-decalinyl, norbornyl, adamantyl and the like.
- “Heterocycloalkyl” (or “heterocyclyl”) means a non-aromatic saturated monocyclic or multicyclic ring system comprising 3 to 10 ring atoms, preferably 5 to 10 ring atoms, in which one or more of the atoms in the ring system is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination. There are no adjacent oxygen and/or sulfur atoms present in the ring system. Preferred heterocycloalkyl groups contain 4, 5 or 6 ring atoms. The prefix aza, oxa or thia before the heterocyclyl root name means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom. Any —NH in a heterocyclyl ring may exist protected such as, for example, as an —N(Boc), —N(CBz), —N(Tos) group and the like; such protections are also considered part of this invention. The heterocyclyl can be optionally substituted by one or more substituents, which may be the same or different, as described herein. The nitrogen or sulfur atom of the heterocyclyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. Thus, the term “oxide,” when it appears in a definition of a variable in a general structure described herein, refers to the corresponding N-oxide, S-oxide, or S,S-dioxide. “Heterocyclyl” also includes rings wherein ═O replaces two available hydrogens on the same carbon atom (i.e., heterocyclyl includes rings having a carbonyl group in the ring). Such ═O groups may be referred to herein as “oxo.” An example of such a moiety is pyrrolidinone (or pyrrolidone):
- As used herein, the term “monocyclic heterocycloalkyl” refers to monocyclic versions of the heterocycloalkyl moieties described herein and include a 4- to 7-membered monocyclic heterocycloalkyl groups comprising from 1 to 4 ring heteroatoms, said ring heteroatoms being independently selected from the group consisting of N, N-oxide, O, S, S-oxide, S(O), and S(O)2. The point of attachment to the parent moiety is to any available ring carbon or ring heteroatom. Non-limiting examples of monocyclic heterocycloalkyl groups include piperidyl, oxetanyl, pyrrolyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, beta lactam, gamma lactam, delta lactam, beta lactone, gamma lactone, delta lactone, and pyrrolidinone, and oxides thereof. Non-limiting examples of lower alkyl-substituted oxetanyl include the moiety:
- It is noted that in hetero-atom containing ring systems of this invention, there are no hydroxyl groups on carbon atoms adjacent to a N, O or S, and there are no N or S groups on carbon adjacent to another heteroatom.
- there is no —OH attached directly to carbons marked 2 and 5.
-
- means containing both
-
- indicate that the indicated line (bond) may be attached to any of the substitutable ring atoms.
- “Oxo” is defined as an oxygen atom that is double bonded to a ring carbon in a cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, or other ring described herein, e.g.,
- As well known in the art, a bond drawn from a particular atom wherein no moiety is depicted at the terminal end of the bond indicates a methyl group bound through that bond to the atom, unless stated otherwise. For example:
- represents
- One or more compounds of the invention may also exist as, or optionally be converted to, a solvate. Preparation of solvates is generally known. Thus, for example, M. Caira et al., J. Pharmaceutical Sci., 93(3), 601-611 (2004) describe the preparation of the solvates of the antifungal fluconazole in ethyl acetate as well as from water. Similar preparations of solvates, and hemisolvate, including hydrates (where the solvent is water or aqueous-based) and the like are described by E. C. van Tonder et al., AAPS PharmSciTech., 5(1), article 12 (2004); and A. L. Bingham et al., Chem. Commun., 603-604 (2001). A typical, non-limiting, process involves dissolving the inventive compound in desired amounts of the desired solvent (for example, an organic solvent, an aqueous solvent, water or mixtures of two or more thereof) at a higher than ambient temperature, and cooling the solution, with or without an antisolvent present, at a rate sufficient to form crystals which are then isolated by standard methods. Analytical techniques such as, for example I.R. spectroscopy, show the presence of the solvent (including water) in the crystals as a solvate (or hydrate in the case where water is incorporated into the crystalline form).
- The term “purified”, “in purified form” or “in isolated and purified form” for a compound refers to the physical state of said compound after being isolated from a synthetic process or natural source or combination thereof. Thus, the term “purified”, “in purified form” or “in isolated and purified form” for a compound refers to the physical state of said compound after being obtained from a purification process or processes described herein or well known to the skilled artisan, and in sufficient purity to be characterized by standard analytical techniques described herein or well known to the skilled artisan.
- This invention also includes the compounds of the invention in isolated and purified form obtained by routine techniques. Polymorphic forms of the compounds of the invention, and of the salts, solvates and prodrugs of the thereof, are intended to be included in the present invention. Certain compounds of the invention may exist in different isomeric forms (e.g., enantiomers, diastereoisomers, atropisomers). The inventive compounds include all isomeric forms thereof, both in pure form and admixtures of two or more, including racemic mixtures.
- In similar manner, unless indicated otherwise, presenting a structural representation of any tautomeric form of a compound which exhibits tautomerism is meant to include all such tautomeric forms of the compound. Accordingly, where compounds of the invention, their salts, and solvates and prodrugs thereof, may exist in different tautomeric forms or in equilibrium among such forms, all such forms of the compound are embraced by, and included within the scope of the invention. Examples of such tautomers include, but are not limited to, ketone/enol tautomeric forms, imine-enamine tautomeric forms, and for example heteroaromatic forms such as the following moieties:
- Where a reaction scheme appearing in an example employs a compound having one or more stereocenters, the stereocenters are indicated with an asterisk, as shown below:
- Accordingly, the above depiction consists of the following pairs of isomers: (i) Trans-isomers ((2R,7aS)-2-methylhexahydro-1H-pyrrolizin-7a-yl)methanamine (Compound ABC-1) and ((2S,7aR)-2-methylhexahydro-1H-pyrrolizin-7a-yl)methanamine (Compound ABC-2); and (ii) Cis-isomers ((2R,7aR)-2-methylhexahydro-1H-pyrrolizin-7a-yl)methanamine (Compound ABC-3) and ((2S,7aS)-2-methylhexahydro-1H-pyrrolizin-7a-yl)methanamine (Compound ABC-4).
- All stereoisomers of the compounds of the invention (including salts and solvates of the inventive compounds and their prodrugs), such as those which may exist due to asymmetric carbons present in a compound of the invention, and including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and diastereomeric forms, are contemplated within the scope of this invention. Individual stereoisomers of the compounds of the invention may be isolated in a pure form, for example, substantially free of other isomers, or may be isolated as an admixture of two or more stereoisomers or as a racemate. The chiral centers of the present invention can have the S or R configuration as defined by the IUPAC 1974 Recommendations. The use of the terms “salt”, “solvate” “prodrug” and the like, is intended to equally apply to salts, solvates and prodrugs of isolated enantiomers, stereoisomer pairs or groups, rotamers, tautomers, or racemates of the inventive compounds.
- Where diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by known methods, for example, by chiral chromatography and/or fractional crystallization, simple structural representation of the compound contemplates all diastereomers of the compound. As is known, enantiomers may also be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individually isolated diastereomers to the corresponding purified enantiomers.
- As the term is employed herein, salts of the inventive compounds, whether acidic salts formed with inorganic and/or organic acids, basic salts formed with inorganic and/or organic bases, salts formed which include zwitterionic character, for example, where a compound contains both a basic moiety, for example, but not limited to, a nitrogen atom, for example, an amine, pyridine or imidazole, and an acidic moiety, for example, but not limited to a carboxylic acid, are included in the scope of the inventive compounds described herein. The formation of pharmaceutically useful salts from basic (or acidic) pharmaceutical compounds are discussed, for example, by S. Berge et al., Journal of Pharmaceutical Sciences (1977) 66(1) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33 201-217; Anderson et al., The Practice of Medicinal Chemistry (1996), Academic Press, New York; in The Orange Book (Food & Drug Administration, Washington, D.C. on their website); and P. Heinrich Stahl, Camille G. Wermuth (Eds.), Handbook of Pharmaceutical Salts: Properties, Selection, and Use, (2002) Int'l. Union of Pure and Applied Chemistry, pp. 330-331. These disclosures are incorporated herein by reference.
- The present invention contemplates all available salts, including salts which are generally recognized as safe for use in preparing pharmaceutical formulations and those which may be formed presently within the ordinary skill in the art and are later classified as being “generally recognized as safe” for use in the preparation of pharmaceutical formulations, termed herein as “pharmaceutically acceptable salts”. Examples of pharmaceutically acceptable acid addition salts include, but are not limited to, acetates, including trifluoroacetate salts, adipates, alginates, ascorbates, aspartates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, cyclopentanepropionates, digluconates, dodecylsulfates, ethanesulfonates, fumarates, glucoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides, hydrobromides, hydroiodides, 2-hydroxyethanesulfonates, lactates, maleates, methanesulfonates, methyl sulfates, 2-naphthalenesulfonates, nicotinates, nitrates, oxalates, pamoates, pectinates, persulfates, 3-phenylpropionates, phosphates, picrates, pivalates, propionates, salicylates, succinates, sulfates, sulfonates (such as those mentioned herein), tartarates, thiocyanates, toluenesulfonates (also known as tosylates) undecanoates, and the like.
- Examples of pharmaceutically acceptable basic salts include, but are not limited to, ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, aluminum salts, zinc salts, salts with organic bases (for example, organic amines) such as benzathines, diethylamine, dicyclohexylamines, hydrabamines (formed with N,N-bis(dehydroabietyl)ethylenediamine), N-methyl-D-glucamines, N-methyl-D-glucamides, t-butyl amines, piperazine, phenylcyclohexyl-amine, choline, tromethamine, and salts with amino acids such as arginine, lysine and the like. Basic nitrogen-containing groups may be converted to an ammonium ion or quarternized with agents such as lower alkyl halides (e.g. methyl, ethyl, propyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g. dimethyl, diethyl, dibutyl, and diamyl sulfates), long chain halides (e.g. decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides), arylalkyl halides (e.g. benzyl and phenethyl bromides), and others.
- All such acid and base salts are intended to be pharmaceutically acceptable salts within the scope of the invention and all acid and base salts are considered equivalent to the free forms of the corresponding compounds for purposes of the scope of the invention.
- A functional group in a compound termed “protected” means that the group is in modified form to preclude undesired side reactions at the protected site when the protected compound is subjected to particular reaction conditions aimed at modifying another region of the molecule. Suitable protecting groups are known, for example, as by reference to standard textbooks, for example, T. W. Greene et al., Protective Groups in organic Synthesis (1991), Wiley, New York.
- In the compounds of the invention, the atoms may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. The present invention is meant to include all suitable isotopic variations of the compounds of the invention. For example, different isotopic forms of hydrogen (H) include protium (1H) and deuterium (2H). Protium is the predominant hydrogen isotope found in nature. Enriching for deuterium may afford certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements, or may provide a compound useful as a standard for characterization of biological samples. Isotopically-enriched compounds of the invention can be prepared without undue experimentation by conventional techniques well known to those skilled in the art or by processes analogous to those described in the Schemes and Examples herein using appropriate isotopically-enriched reagents and/or intermediates.
- The present invention also embraces isotopically-labeled compounds of the present invention which are structurally identical to those recited herein, but for the fact that a statistically significant percentage of one or more atoms in that form of the compound are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number of the most abundant isotope usually found in nature, thus altering the naturally occurring abundance of that isotope present in a compound of the invention. Examples of isotopes that can be preferentially incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, iodine, fluorine and chlorine, for example, but not limited to: 2H, 3H, 11C, 13C, 14C, 13N, 15N, 15O, 17O, 18O, 31P, 32P, 35S, 18F, and 36Cl, 123I and 125I. It will be appreciated that other isotopes also may be incorporated by known means.
- Certain isotopically-labeled compounds of the invention (e.g., those labeled with 3H, 11C and 14C) are recognized as being particularly useful in compound and/or substrate tissue distribution assays using a variety of known techniques. Tritiated (i.e., 3H) and carbon-14 (i.e., 14C) isotopes are particularly preferred for their ease of preparation and detection. Further, substitution of a naturally abundant isotope with a heavier isotope, for example, substitution of protium with deuterium (i.e., 2H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances. Isotopically labeled compounds of the invention can generally be prepared by following procedures analogous to those disclosed in the reaction Schemes and/or in the Examples herein below, by substituting an appropriate isotopically labeled reagent for a non-isotopically labeled reagent, or by well-known reactions of an appropriately prepared precursor to the compound of the invention which is specifically prepared for such a “labeling” reaction. Such compounds are included also in the present invention.
- The term “composition” is intended to encompass a product comprising the specified ingredients in the specified amounts, and any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
- The term “pharmaceutical composition” as used herein encompasses both the bulk composition and individual dosage units comprised of one, or more than one (e.g., two), pharmaceutically active agents such as, for example, a compound of the present invention (optionally together with an additional agent as described herein), along with any pharmaceutically inactive excipients. As will be appreciated by those of ordinary skill in the art, excipients are any constituent which adapts the composition to a particular route of administration or aids the processing of a composition into a dosage form without itself exerting an active pharmaceutical effect. The bulk composition and each individual dosage unit can contain fixed amounts of the aforesaid one, or more than one, pharmaceutically active agents. The bulk composition is material that has not yet been formed into individual dosage units.
- It will be appreciated that pharmaceutical formulations of the invention may comprise more than one compound of the invention (or a pharmaceutically acceptable salt thereof), for example, the combination of two or three compounds of the invention, each present in such a composition by adding to the formulation the desired amount of the compound in a pharmaceutically acceptably pure form. It will be appreciated also that in formulating compositions of the invention, a composition may comprise, in addition to one or more of compounds of the invention, one or more other agents which also have pharmacological activity, as described herein.
- While formulations of the invention may be employed in bulk form, it will be appreciated that for most applications the inventive formulations will be incorporated into a dosage form suitable for administration to a patient, each dosage form comprising an amount of the selected formulation which contains an effective amount of one or more compounds of the invention. Examples of suitable dosage forms include, but are not limited to, dosage forms adapted for: (i) oral administration, e.g., a liquid, gel, powder, solid or semi-solid pharmaceutical composition which is loaded into a capsule or pressed into a tablet and may comprise additionally one or more coatings which modify its release properties, for example, coatings which impart delayed release or formulations which have extended release properties; (ii) a dosage form adapted for intramuscular administration (IM), for example, an injectable solution or suspension, and which may be adapted to form a depot having extended release properties; (iii) a dosage form adapted for intravenous administration (IV), for example, a solution or suspension, for example, as an IV solution or a concentrate to be injected into a saline IV bag; (iv) a dosage form adapted for administration through tissues of the oral cavity, for example, a rapidly dissolving tablet, a lozenge, a solution, a gel, a sachets or a needle array suitable for providing intramucosal administration; (v) a dosage form adapted for administration via the mucosa of the nasal or upper respiratory cavity, for example a solution, suspension or emulsion formulation for dispersion in the nose or airway; (vi) a dosage form adapted for transdermal administration, for example, a patch, cream or gel; (vii) a dosage form adapted for intradermal administration, for example, a microneedle array; and (viii) a dosage form adapted for delivery via rectal or vaginal mucosa, for example, a suppository.
- For preparing pharmaceutical compositions comprising compounds of the invention, generally the compounds of the invention will be combined with one or more pharmaceutically acceptable excipients. These excipients impart to the composition properties which make it easier to handle or process, for example, lubricants or pressing aids in powdered medicaments intended to be tableted, or adapt the formulation to a desired route of administration, for example, excipients which provide a formulation for oral administration, for example, via absorption from the gastrointestinal tract, transdermal or transmucosal administration, for example, via adhesive skin “patch” or buccal administration, or injection, for example, intramuscular or intravenous, routes of administration. These excipients are collectively termed herein “a carrier”. Typically formulations may comprise up to about 95 percent active ingredient, although formulations with greater amounts may be prepared.
- Pharmaceutical compositions can be solid, semi-solid or liquid. Solid form preparations can be adapted to a variety of modes of administration, examples of which include, but are not limited to, powders, dispersible granules, mini-tablets, beads, which can be used, for example, for tableting, encapsulation, or direct administration. Liquid form preparations include, but are not limited to, solutions, suspensions and emulsions which for example, but not exclusively, can be employed in the preparation of formulations intended for parenteral injection, for intranasal administration, or for administration to some other mucosal membrane. Formulations prepared for administration to various mucosal membranes may also include additional components adapting them for such administration, for example, viscosity modifiers.
- Aerosol preparations, for example, suitable for administration via inhalation or via nasal mucosa, may include solutions and solids in powder form, which may be in combination with a pharmaceutically acceptable propellant, for example, an inert compressed gas, e.g. nitrogen. Also included are solid form preparations which are intended to be converted, shortly before use, to a suspension or a solution, for example, for oral or parenteral administration. Examples of such solid forms include, but are not limited to, freeze dried formulations and liquid formulations adsorbed into a solid absorbent medium.
- The compounds of the invention may also be deliverable transdermally or transmucosally, for example, from a liquid, suppository, cream, foam, gel, or rapidly dissolving solid form. It will be appreciated that transdermal compositions can take also the form of creams, lotions, aerosols and/or emulsions and can be provided in a unit dosage form which includes a transdermal patch of any know in the art, for example, a patch which incorporates either a matrix comprising the pharmaceutically active compound or a reservoir which comprises a solid or liquid form of the pharmaceutically active compound.
- Examples of pharmaceutically acceptable carriers and methods of manufacture for various compositions mentioned above may be found in A. Gennaro (ed.), Remington: The Science and Practice of Pharmacy, 20th Edition, (2000), Lippincott Williams & Wilkins, Baltimore, Md.
- Preferably, the pharmaceutical preparation is in a unit dosage form. In such form, the preparations subdivided into suitably sized unit doses containing appropriate quantities of the active component, e.g., an effective amount to achieve the desired purpose.
- The actual dosage employed may be varied depending upon the requirements of the patient and the severity of the condition being treated. Determination of the proper dosage regimen for a particular situation is within the skill in the art. For convenience, the total daily dosage may be divided and administered in portions during the day as required.
- In accordance with the present invention, antagonism of adenosine A2a and/or A2b receptors is accomplished by administering to a patient in need of such therapy an effective amount of one or more compounds of the invention, or a pharmaceutically acceptable salt thereof.
- In some embodiments it is preferred for the compound to be administered in the form of a pharmaceutical composition comprising the compound of the invention, or a salt thereof, and at least one pharmaceutically acceptable carrier (described herein). It will be appreciated that pharmaceutically formulations of the invention may comprise more than one compound of the invention, or a salt thereof, for example, the combination of two or three compounds of the invention, or, additionally or alternatively, another active agent such as those described herein, each present by adding to the formulation the desired amount of the compound or a salt thereof (or agent, where applicable) which has been isolated in a pharmaceutically acceptably pure form.
- As mentioned above, administration of a compound of the invention to effect antagonism of A2a and/or A2b receptors is preferably accomplished by incorporating the compound into a pharmaceutical formulation incorporated into a dosage form, for example, one of the above-described dosage forms comprising an effective amount of at least one compound of the invention (e.g., 1, 2 or 3, or 1 or 2, or 1, and usually 1 compound of the invention), or a pharmaceutically acceptable salt thereof. Methods for determining safe and effective administration of compounds which are pharmaceutically active, for example, a compound of the invention, are known to those skilled in the art, for example, as described in the standard literature, for example, as described in the “Physicians' Desk Reference” (PDR), e.g., 1996 edition (Medical Economics Company, Montvale, N.J. 07645-1742, USA), the Physician's Desk Reference, 56th Edition, 2002 (published by Medical Economics company, Inc. Montvale, N.J. 07645-1742), or the Physician's Desk Reference, 57th Edition, 2003 (published by Thompson PDR, Montvale, N.J. 07645-1742); the disclosures of which is incorporated herein by reference thereto. The amount and frequency of administration of the compounds of the invention and/or the pharmaceutically acceptable salts thereof will be regulated according to the judgment of the attending clinician considering such factors as age, condition and size of the patient as well as severity of the symptoms being treated. Compounds of the invention can be administered at a total daily dosage of up to 1,000 mg, which can be administered in one daily dose or can be divided into multiple doses per 24 hour period, for example, two to four doses per day.
- As those of ordinary skill in the art will appreciate, an appropriate dosage level for a compound (or compounds) of the invention will generally be about 0.01 to 500 mg per kg patient body weight per day which can be administered in single or multiple doses. A suitable dosage level may be about 0.01 to 250 mg/kg per day, about 0.05 to 100 mg/kg per day, or about 0.1 to 50 mg/kg per day. Within this range the dosage may be 0.05 to 0.5, 0.5 to 5 or 5 to 50 mg/kg per day. For oral administration, the compositions may be provided in the form of tablets containing 1.0 to 1000 milligrams of the active ingredient, particularly 1.0, 5.0, 10.0, 15.0, 20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0, and 1000.0 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. The compounds may be administered on a regimen of 1 to 4 times per day, or may be administered once or twice per day.
- Those skilled in the art will appreciate that treatment protocols utilizing at least one compound of the invention can be varied according to the needs of the patient. Thus, compounds of the invention used in the methods of the invention can be administered in variations of the protocols described above. For example, compounds of the invention can be administered discontinuously rather than continuously during a treatment cycle.
- In general, in whatever form administered, the dosage form administered will contain an amount of at least one compound of the invention, or a salt thereof, which will provide a therapeutically effective serum level of the compound in some form for a suitable period of time such as at least 2 hours, more preferably at least four hours or longer. In general, as is known in the art, dosages of a pharmaceutical composition providing a therapeutically effective serum level of a compound of the invention can be spaced in time to provide serum level meeting or exceeding the minimum therapeutically effective serum level on a continuous basis throughout the period during which treatment is administered. As will be appreciated the dosage form administered may also be in a form providing an extended release period for the pharmaceutically active compound which will provide a therapeutic serum level for a longer period, necessitating less frequent dosage intervals. As mentioned above, a composition of the invention can incorporate additional pharmaceutically active components or be administered simultaneously, contemporaneously, or sequentially with other pharmaceutically active agents as may be additionally needed or desired in the course of providing treatment. As will be appreciated, the dosage form administered may also be in a form providing an extended release period for the pharmaceutically active compound which will provide a therapeutic serum level for a longer period, necessitating less frequent dosage intervals.
- The compounds of the present invention can be prepared readily according to the following schemes and specific examples, or modifications thereof, using readily available starting materials, reagents and conventional synthetic procedures. In these reactions, it is also possible to make use of variants which are themselves known to those of ordinary skill in this art but are not mentioned in detail. The general procedures for making the compounds claimed in this invention can be readily understood and appreciated by one skilled in the art from viewing the following Schemes and descriptions.
- One general strategy for the synthesis of compounds of type G1.6 is via the four-step procedure shown in General Scheme 1, wherein R4 corresponds to ring A in Formula (I) and wherein R1, R2, and ring A are as defined in Formula (I). In the first step, amino benzonitriles G1.1 can be treated with 1-(isocyanatomethyl)-2,4-dimethoxybenzene in solvents such as the combination of dichloromethane and pyridine to form intermediate ureas G1.2. In the second step, these ureas can be dehydrated to the corresponding carbodiimides G1.3 in the presence of triphenylphosphine, carbon tetrabromide, and triethylamine in a solvent such as dichloromethane. In the third step, treatment of carbodiimides G1.3 with a hydrazide of the type G1.4 in the presence of acetic acid in a solvent such as dichloromethane or dioxane, produces products of the type G1.5. In the fourth step, the 2,4-dimethoxybenzyl group of G1.4 is removed under acidic conditions to provide products of type G1.6, which can be purified by silica gel chromatography, preparative reversed phase HPLC, and/or chiral SFC.
- One general strategy for the synthesis of compounds of type G2.5 is via the three-step procedure shown in General Scheme 2, wherein RA(n) corresponds to RA1, RA2, RA3, and RA5 in Formula (I) and wherein R1, R2, R3 and RA(n) (as RA1, RA2, RA3, and RA5) are as defined in Formula (I). In the first step, protected cyclic amines G2.1 can be converted into unprotected amines G2.2 through carefully controlled treatment with acid. Acids such as formic acid in the absence of solvent or hydrochloric acid in the presence of MeOH or DCM, can be used. In the second step, intermediates of type G2.2 can be converted into intermediates of type G2.4 through a transition-metal catalyzed C—N coupling reaction with aryl bromides G2.3. The reaction is performed under deoxygenated conditions with palladium catalysts such as, tert-butyl X-Phos Third Generation Precatalyst, a base such as sodium tert-butoxide, and a solvent such as THF, at the appropriate temperature. In the third step, the 2,4-dimethoxybenzyl group of G2.4 is removed under acidic conditions to provide products of type G2.5, which can be purified by silica gel chromatography, preparative reversed-phase HPLC, and/or chiral SFC.
- One general strategy for the synthesis of compounds of type G3.6 is via a four-step procedure shown in General Scheme 3, wherein R4 corresponds to ring A in Formula (I) and wherein R1, R2, and ring A are as defined in Formula (I). In the first step, amino benzoic acids G3.1 can be converted into amino quinazolines G3.2 via treatment with cyanamide in the presence of aqueous HCl in a solvent such as EtOH. In the second step, intermediates of type G3.2 can be converted into intermediates of type G3.3 through coupling with 1,2,4-triazole, following treatment of G3.2 with phosphorous (V) oxychloride in a solvent such as acetonitrile. In the third step, intermediates of type G3.3 can be treated with hydrazides G3.4 in a solvent such as THF, to provide products of type G3.5. In the fourth step, intermediates of type G3.5 can undergo a rearrangement upon heating in neat N,O-Bis(trimethylsilyl)acetamide (BSA) to form products of type G3.6. Products of type G3.6 can be purified by silica gel chromatography, preparative reversed-phase HPLC, and/or chiral SFC.
- One general strategy for the synthesis of compounds of type G4.5 is via a three-step procedure outlined in General Scheme 4, wherein R1, R2, R3, RA1, RA2, and RA3 are defined in Formula (I). Heteroaryl cyclohexanol G4.1 can be converted into the corresponding cyclohexanone G4.2 via oxidation with Dess-Martin periodinane. In the second step, intermediates of type G4.2 can undergo treatment with an R3—Li G4.3 at low temperature, to provide products of type G4.4. In the third step, the 2,4-dimethoxybenzyl group of G2.4 can be removed with DDQ to provide products of type G4.5, which can be purified by silica gel chromatography, preparative reversed-phase HPLC, and/or chiral SFC.
- Abbreviations used in the experimentals may include, but are not limited to, the following:
-
18-crown-6 1,4,7,10,13,16-hexaoxacyclooctadecane ° C. Degrees Celsius AcOH Acetic acid aq. Aqueous Atm Atmospheres Boc2O Di-tert-butyl dicarbonate BSA N,O-Bis(trimethylsilyl)acetamide CD3OD Deuterated Methanol-d4 DCM Dichloromethane DDQ 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone DEA Diethylamine DIAD Diisopropyl diazene-1,2-dicarboxylate DIBAL Diisobutylaluminium hydride DIPEA N,N-Diisopropylethylamine DMAP 4-(dimethylamino)-pyridine DMF Dimethylformamide DMP Dess-Martin periodinane DMSO Dimethyl Sulfoxide DMSO-d6 Deuterated Dimethyl Sulfoxide dppf Bis(diphenylphosphino)ferrocene ES Electrospray Ionization Et2O Diethylether EtOAc Ethyl Acetate EtOH Ethanol h Hours HPLC High Performance Liquid Chromatography M Molar MeCN Acetonitrile MeOD-d4 Deuterated Methanol MeOH Methanol MHz Megahertz min Minutes mL Milliliters MS Mass Spectroscopy MsCl p-Toluenesulfonyl chloride NaH Sodium hydride NBS N-Bromosuccinimide nm Nanometers NMR Nuclear Magnetic Resonance Pd/C Palladium on Carbon PPTS Pyrdinium para-toluenesulfonate p-TsOH 4-Methylbenzenesulfonic acid Py Pyridine rac racemic SFC Supercritical Fluid (CO2) Chromatography T3P Tripropyl phosphonic anhydride tBuXPhos-Pd G3 Tf2O Trifluoromethanesulfonic anhydride TFA Trifluoroacetic acid TFE 2,2,2-Trifluoroethanol THF Tetrahydrofuran THP (tetrahydro-2H-pyran-2-yl)oxy TLC Thin Layer Chromatography - Unless otherwise noted, all reactions were magnetically stirred and performed under an inert atmosphere such as nitrogen or argon.
- Unless otherwise noted, diethyl ether used in the experiments described below was Fisher ACS certified material and stabilized with BHT.
- Unless otherwise noted, “degassed” refers to a solvent from which oxygen has been removed, generally by bubbling an inert gas such as nitrogen or argon through the solution for 10 to 15 minutes with an outlet needle to normalize pressure.
- Unless otherwise noted, “concentrated” means evaporating the solvent from a solution or mixture using a rotary evaporator or vacuum pump.
- Unless otherwise noted, “evaporated” means evaporating using a rotary evaporator or vacuum pump.
- Unless otherwise noted, silica gel chromatography was carried out on an ISCO®, Analogix®, or Biotage® automated chromatography system using a commercially available cartridge as the column. Columns were usually filled with silica gel as the stationary phase. Reverse phase preparative HPLC conditions can be found at the end of the experimental section. Aqueous solutions were concentrated on a Genevac® evaporator or were lyophilized.
- Unless otherwise noted, proton nuclear magnetic resonance (1H NMR) spectra and proton-decoupled carbon nuclear magnetic resonance (13C{1H} NMR) spectra were recorded on 400, 500, or 600 MHz Bruker or Varian NMR spectrometers at ambient temperature. All chemical shifts (6) were reported in parts per million (ppm). Proton resonances were referenced to residual protium in the NMR solvent, which can include, but is not limited to, CDCl3, DMSO-d6, and MeOD-d4. Carbon resonances are referenced to the carbon resonances of the NMR solvent. Data are represented as follows: chemical shift, multiplicity (br=broad, br s=broad singlet, s=singlet, d=doublet, dd=doublet of doublets, ddd=doublet of doublet of doublets, t=triplet, q=quartet, m=multiplet), coupling constants (J) in Hertz (Hz), integration.
- Intermediate 1: rac-3-(4-bromo-1H-pyrazol-1-yl)-2-methylbutan-2-ol
- To a stirred solution of 4-bromo-1H-pyrazole (1.00 g, 6.80 mmol) in DMF (3.40 ml) was added cesium carbonate (2.22 g, 6.80 mmol) and 2,2,3-trimethyloxirane (820 mg, 9.52 mmol). The mixture was stirred and heated at 90° C. for 4 h. The mixture was cooled to room temperature, filtered, and the solvents of the filtrate were evaporated. The residue was purified by silica gel chromatography with 5-100% EtOAc in hexanes as eluent to afford rac-3-(4-bromo-1H-pyrazol-1-yl)-2-methylbutan-2-ol. LCMS (C8H13BrN2O) (ES, m/z) [M+H]+: 233, 235.
- The intermediates in the following Table 1 were prepared in a manner similar to that of Intermediate 1 from the appropriate pyrazole and epoxide.
-
- To a stirred solution of 1-(hydroxymethyl)cyclobutan-1-ol (9.00 g, 88.0 mmol) in DCM (260 mL) at 0° C. was added triethylamine (17.2 ml, 123 mmol) followed by methanesulfonyl chloride (7.0 mL, 90 mmol). The mixture was stirred at 0° C. for 10 min. The mixture was then warmed to room temperature and stirred for 15 min. The mixture was then partitioned with water. The layers were separated and the organic layer was washed with brine. The organic layer was dried over anhydrous MgSO4, filtered, and evaporated to afford (1-hydroxycyclobutyl)methyl methanesulfonate.
-
- To a solution of 4-bromo-1H-pyrazole (7.70 g, 52.4 mmol) in DMF (60 ml) at 0° C. was added NaH (60% in mineral oil, 2.30 g, 57.6 mmol) portionwise. The mixture was stirred at 0° C. under nitrogen for 30 min. To the mixture was added a solution of (1-hydroxycyclobutyl)methyl methanesulfonate (13.1 g, 72.8 mmol) in DMF (20 ml). The mixture was stirred and heated at 90° C. for 16 h. The mixture was quenched with water (70 mL), then extracted with EtOAc three times. The organic layer was dried over anhydrous MgSO4, filtered, and the solvents of the filtrate were evaporated. The residue was purified by silica gel chromatography with 0-30% EtOAc in petroleum ether as eluent, to afford 1-((4-bromo-1H-pyrazol-1-yl)methyl)cyclobutan-1-ol. LCMS (C8H11BrN2O) (ES, m/z): 231, 233 [M+H]+.
-
- Step 1 of the synthesis of Intermediate 12 was conducted similar to step 1 of the synthesis of Intermediate 11 from the appropriate starting materials to afford (3-methyloxetan-3-yl)methyl methanesulfonate.
-
- To a solution of 4-bromo-1H-pyrazole (5.04 g, 34.3 mmol) in DMF (114 mL) was added (3-methyloxetan-3-yl)methyl methanesulfonate (6.18 g, 34.3 mmol) and cesium carbonate (15.6 g, 48.0 mmol). The mixture was stirred and heated at 60° C. for 6 h. The solvents were evaporated. To the residue was added DCM (100 mL), and the mixture was filtered. The solvents of the filtrate were evaporated. The residue was purified by silica gel chromatography with 0-100% EtOAc in hexane to afford 4-bromo-1-((3-methyloxetan-3-yl)methyl)-1H-pyrazole. LCMS (C8H11BrN2O) (ES, m/z): 231, 233 [M+H]+.
- Intermediate 13, shown in the following Table 2, was prepared in a manner similar to that of Intermediate 12 from the appropriate starting materials.
-
- To a solution of 2-bromo-5,8-dioxaspiro[3.4]octane (0.500 g, 2.59 mmol) and 4-bromo-1H-pyrazole (0.761 g, 5.18 mmol) in DMF (2.6 mL) in an 8 mL vial was added potassium carbonate (1.07 g, 7.77 mmol) and 18-crown-6 (0.137 g, 0.518 mmol). The mixture was stirred and heated at 90° C. After 5 min, the mixture was cooled to room temperature, and to the mixture was added additional 4-bromo-1H-pyrazole (400 mg, 2.72 mmol). The mixture was stirred and heated at 90° C. for 48 h. The mixture was then cooled to room temperature and partitioned between EtOAc (25 mL) and water (25 mL). The layers were separated and the organic layer was washed with brine. The two aqueous layers were combined and extracted with EtOAc (15 mL). The organic layers were combined, washed with brine twice, dried over anhydrous Na2SO4, filtered, and the solvents of the filtrate were evaporated. The residue was purified by silica gel chromatography with 0-50% EtOAc in hexanes to afford 4-bromo-1-(5,8-dioxaspiro[3.4]octan-2-yl)-1H-pyrazole.
- LCMS (C9H12BrN2O2) (ES, m/z): 259, 261 [M+H]+.
-
- To a solution of 4-bromo-1-(5,8-dioxaspiro[3.4]octan-2-yl)-1H-pyrazole (270 mg, 1.042 mmol) and PPTS (131 mg, 0.521 mmol) in dioxane (2.6 mL) was added water (2.6 mL). The mixture was stirred and heated at 85° C. for 95 h. The mixture was cooled to room temperature. The mixture was partitioned between EtOAc and saturated aqueous sodium bicarbonate. The layers were separated, and the aqueous layer was extracted with EtOAc. The organic layers were combined, washed with brine, dried over anhydrous Na2SO4, filtered, and the solvents were evaporated. The residue was purified by silica gel chromatography with 0-100% EtOAc in hexane to afford 3-(4-bromo-1H-pyrazol-1-yl)cyclobutanone. LCMS (C7H8BrN2O) (ES, m/z): 215, 217 [M+H]+.
-
- A solution of 3-(4-bromo-1H-pyrazol-1-yl)cyclobutanone (129 mg, 0.600 mmol) in diethyl ether (3.5 ml) was cooled to 0° C. To the stirred mixture was added methylmagnesium bromide (3 M in diethyl ether, 0.240 ml, 0.720 mmol) dropwise. The mixture was stirred for 16 h, allowing the ice bath to expire. The mixture was partitioned between EtOAc and 20% aqueous citric acid and stirred for 2 h. The layers were separated and the aqueous layer was extracted with EtOAc. The organic layers were combined, washed with brine, dried over anhydrous Na2SO4, filtered, and the solvents of the filtrate were evaporated. The residue was purified by silica gel chromatography with 0-60% EtOAc in hexanes as eluent to afford (1s, 3s)-3-(4-bromo-1H-pyrazol-1-yl)-1-methylcyclobutanol. LCMS (C8H12BrN2O) (ES, m/z): 231, 233 [M+H]+.
-
- To a reaction vial were added 4-bromo-1H-pyrazole (1.50 g, 10.2 mmol), 4-iodotetrahydro-2H-pyran (2.16 g, 10.2 mmol), potassium carbonate (1.41 g, 10.2 mmol) and DMF (15 mL). The mixture was stirred and heated at 100° C. for 16 h. The mixture was purified by silica gel chromatography with 0-50% EtOAc in petroleum ether as eluent, to afford 4-bromo-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole. LCMS (C8H11BrN2O) (ES, m/z): 231, 233 [M+H]+.
-
- To a 200 mL round bottom flask was added 4-bromo-3-methyl-1H-pyrazole (1.00 g, 6.21 mmol) and THF (62.1 ml). The mixture was stirred under an atmosphere of nitrogen. The mixture was cooled at 0° C. To the mixture was added NaH (0.311 g, 7.76 mmol) portionwise. The mixture was slowly warmed to room temperature over 30 min. The mixture was then cooled at 0° C., and to the mixture was added trityl chloride (1.90 g, 6.83 mmol). The mixture was stirred for 16 h at room temperature. The mixture was quenched with water (60 mL) and diluted with EtOAc (60 mL). The layers were separated and the aqueous layer was further extracted with EtOAc (2×50 mL). The combined organic layers were dried over anhydrous MgSO4, filtered, and the solvents of the filtrate were evaporated. The residue was purified by silica gel chromatography with 0-25% EtOAc in hexanes as eluent to afford 4-bromo-3-methyl-1-trityl-1H-pyrazole and 4-bromo-5-methyl-1-trityl-1H-pyrazole as a mixture of regioisomers. LCMS (C23H19BrN2) (ES, m/z): 425, 427 [M+Na]+.
-
- To a stirred mixture of 4-bromo-5-(difluoromethyl)-1H-pyrazole (250 mg, 1.27 mmol), trityl chloride (460 mg, 1.65 mmol) and pyridine (201 mg, 2.54 mmol) in DCM (4 mL) was added DMAP (15.5 mg, 0.127 mmol). The mixture was stirred at room temperature for 16 h. The mixture was washed with water (5 mL) and aqueous saturated NH4Cl (5 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and the solvents of the filtrate were evaporated. The residue was purified by silica gel chromatography with 0-50% EtOAc in petroleum ether as eluent to afford 4-bromo-5-(difluoromethyl)-1-trityl-1H-pyrazole. LCMS (C23H17BrF2N2) (ES, m/z): 461, 463 [M+Na]+.
-
- To a solution of 4-bromo-5-(difluoromethyl)-1H-pyrazole (240 mg, 1.218 mmol) in DMF (60 ml) were added cesium carbonate (595 mg, 1.828 mmol) and tetrahydro-2H-pyran-4-yl methanesulfonate (329 mg, 1.828 mmol). The mixture was stirred and heated at 80° C. under nitrogen for 3 h. The mixture was cooled to room temperature and diluted with water (100 mL). The mixture was extracted with EtOAc three times. The organic layer was washed with water followed by brine, dried over anhydrous MgSO4, and filtered. The solvents of the filtrate were evaporated. The resulting residue was purified by silica gel chromatography with 0-90% EtOAc in hexanes as eluent to afford a mixture of 4-bromo-3-(difluoromethyl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole and 4-bromo-5-(difluoromethyl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole.
-
- To a solution of 4-bromo-1H-pyrazole (2.00 g, 13.6 mmol) in DMF (20 mL) was added methyl 2-bromo-2-methylpropanoate (1.76 mL, 13.6 mmol) followed by cesium carbonate (8.87 g, 27.2 mmol). The mixture was heated at 80° C. for 18 h. The mixture was filtered, and the filter cake was washed with DCM. The combined filtrates were evaporated. The resulting residue was purified by silica gel chromatography with 10% EtOAc in hexanes as eluent to afford methyl 2-(4-bromo-1H-pyrazol-1-yl)-2-methylpropanoate. LCMS (C8H11BrN2O2) (ES, m/z): 247, 249 [M+H]+.
-
- To a solution of methyl 2-(4-bromo-1H-pyrazol-1-yl)-2-methylpropanoate (1.74 g, 7.04 mmol) in EtOH (35 ml) was added sodium borohydride (0.799 g, 21.1 mmol) at 0° C. The mixture was stirred at room temperature for 2 h. The mixture was diluted in DCM (50 mL), washed with water and brine solution. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to afford 2-(4-bromo-1H-pyrazol-1-yl)-2-methylpropan-1-ol.
- LCMS (C7H11BrN2O) (ES, m/z): 219, 221 [M+H]+.
- Intermediate 20 in the following Table 3 was prepared in a manner similar to that described for the synthesis of Intermediate 19 from the appropriate starting materials.
-
- Step 1 of the synthesis of Intermediate 21 was conducted in manner similar to that used in the synthesis of Intermediate 1 from the appropriate starting materials to afford 1-(3-cyclopropyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol.
-
- To a solution of 1-(3-cyclopropyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol (1.55 g, 8.60 mmol) in DCM (86 mL) was added 1,3-dibromo-5,5-dimethylhydantoin (1.23 g, 4.30 mmol). The mixture was stirred at room temperature for 30 min. The solvents were evaporated, and the resulting residue was purified by silica gel chromatography with 10-90% EtOAc in hexanes to afford 1-(4-bromo-3-cyclopropyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol. LCMS (C10H15BrN2O) (ES, m/z): 259, 261 [M+H]+.
-
- Step 1 of the synthesis of Intermediate 22 was conducted in a manner analogous to step 2 of the synthesis of Intermediate 21 from the appropriate starting materials to afford (4-bromo-1-ethyl-1H-pyrazol-3-yl)methanol. LCMS (C6H9BrN2O) (ES, m/z): 205, 207 [M+H]+.
-
- To a stirred solution of (4-bromo-1-ethyl-1H-pyrazol-3-yl)methanol (570 mg, 2.78 mmol) in DCM (27 mL) was added 3,4-dihydro-2H-pyran (468 mg, 5.56 mmol), followed by the addition of 4-methylbenzenesulfonic acid (polymer supported) (239 mg, 1.39 mmol). The mixture was stirred at room temperature for 2 h. The mixture was filtered, and the filtrate was loaded directly onto a silica gel column and purified with 0-60% EtOAc in hexane as eluent to afford rac-4-bromo-1-ethyl-3-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-pyrazole. LCMS (C11H17BrN2O2) (ES, m/z): 289, 291 [M+H]+.
-
- To a stirred solution of rac-(1-((tetrahydro-2H-pyran-2-yl)oxy)cyclobutyl)methanol (8.00 g, 43.0 mmol) in DCM (150 mL) at 0° C. was added triethylamine (8.38 mL, 60.1 mmol) followed by methanesulfonyl chloride (4.02 mL, 51.5 mmol). The mixture was stirred at 0° C. for 10 min and then warmed to room temperature and stirred for 40 min. The mixture was then partitioned with water. The layers were separated, and the organic layer was washed with brine. The organic layer was dried over anhydrous MgSO4, filtered, and evaporated to afford rac-(1-((tetrahydro-2H-pyran-2-yl)oxy)cyclobutyl)methyl methanesulfonate, LCMS (C11H20O5S) (ES, m/z): 287 [M+Na]+.
-
- To a solution of 4-bromo-1H-pyrazole (5.40 g, 36.7 mmol) in DMF (60 mL) at 0° C. was added NaH (60% in mineral oil, 1.62 g, 40.4 mmol) portionwise. The mixture was stirred at 0° C. under nitrogen for 1 h. To the mixture was added rac-(1-((tetrahydro-2H-pyran-2-yl)oxy)cyclobutyl)methyl methanesulfonate (10.7 g, 40.4 mmol). The mixture was stirred and heated at 90° C. under nitrogen for 16 h. The mixture was quenched with water (200 mL) and extracted with EtOAc three times. The combined organic layers were washed with water followed by brine. The organic layer was dried over anhydrous MgSO4, filtered, and evaporated. The resulting residue was purified by silica gel chromatography with 0-30% EtOAc in petroleum ether as eluent to afford rac-4-bromo-1-((1-((tetrahydro-2H-pyran-2-yl)oxy)cyclobutyl)methyl)-1H-pyrazole (Intermediate 23). LCMS (C13H19BrN2O2) (ES, m/z): 315, 317 [M+H]+.
-
- The mixture of 1-(4-bromo-3-methyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol and 1-(4-bromo-5-methyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol (Intermediate 7) was separated by SFC (Chiral Technologies IG 21×250 mm column with 15% (MeOH w/0.1% NH4OH modifier) as cosolvent) to afford 1-(4-bromo-3-methyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol (Intermediate 24, first eluting peak) and 1-(4-bromo-5-methyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol (Intermediate 25, second eluting peak).
- For Intermediate 24: LCMS (C13H19BrN2O2) (ES, m/z): 233, 235 [M+H]+.
- For Intermediate 25: LCMS (C8H13BrN2O) (ES, m/z): 233, 235 [M+H]+.
- Intermediate 26 and Intermediate 27 in the following Table 4 were prepared in a manner analogous to the preparation of Intermediate 24 and Intermediate 25 by SFC separation of the racemic mixture Intermediate 1.
-
TABLE 4 Observed Inter- Structure SFC m/z mediate Name Conditions [M + H]+ 26 Peak 1; Chiral Technologies AD-H 50 × 250 mm column with 35% MeOH as co-solvent 233, 235 (S or R)-3-(4-bromo-1H-pyrazol- 1-yl)-2-methylbutan-2-ol 27 Peak 2; Chiral Technologies AD-H 50 × 250 mm column with 35% MeOH as co-solvent 233, 235 (R or S)-3-(4-bromo-1H-pyrazol- 1-yl)-2-methylbutan-2-ol -
- To a solution of 2-bromocyclobutanone (16.2 g, 109 mmol) in MeCN (30 mL) was added 4-bromo-1H-pyrazole (8.00 g, 54.4 mmol) and potassium carbonate (30.1 g, 218 mmol). The mixture was stirred at 20° C. for 10 h. The mixture was filtered, and the solvents of the filtrate were evaporated. The residue was purified by reversed-phase HPLC (Waters SunFire C18 OBD Prep Column, 19 mm×100 mm MeCN/water (with 0.1% TFA modifier) as eluent) to afford rac-2-(4-bromo-1H-pyrazol-1-yl)cyclobutanone. LCMS (C7H7BrN2O) (ES, m/z) [M+H]+: 215, 217.
-
- Methylmagnesium bromide (0.248 ml, 0.744 mmol, 3 M in diethyl ether) was added to a stirred mixture of rac-2-(4-bromo-1H-pyrazol-1-yl)cyclobutanone (Intermediate 28) (80.0 mg, 0.372 mmol) in THF (2 mL) at −78° C., and the mixture was stirred at that temperature for 3 h. The reaction was quenched with aqueous saturated NH4Cl (2 mL), and the desired layer was extracted from the mixture with EtOAc (2×20 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and evaporated. The resulting residue was purified by preparative silica gel TLC with 30% EtOAc in petroleum ether as eluent to afford 2-(4-bromo-1H-pyrazol-1-yl)-1-methylcyclobutanol. LCMS (C8H11BrN2O) (ES, m/z) [M+H]+: 231, 233.
-
- To a stirred mixture of trimethoxymethane (592 mg, 5.58 mmol) and rac-2-(4-bromo-1H-pyrazol-1-yl)cyclobutanone (Intermediate 28) (600 mg, 2.79 mmol) in MeOH (5 mL) was added 4-methylbenzenesulfonic acid hydrate (53.1 mg, 0.279 mmol). The mixture was stirred at 28° C. for 12 h. The mixture was diluted with EtOAc (50 mL) and washed with water (30 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and the solvents of the filtrate were evaporated. The resulting residue was purified by silica gel chromatography with 0-10% EtOAc in petroleum ether as eluent to afford rac-4-bromo-1-(2,2-dimethoxycyclobutyl)-1H-pyrazole.
- LCMS (C9H13BrN2O2) (ES, m/z) [M+H]+: 261, 263.
-
- To a stirred solution of rac-(1-((tetrahydro-2H-pyran-2-yl)oxy)cyclobutyl)methanol (1.00 g, 5.37 mmol), 4-bromo-5-methyl-1H-pyrazole (0.864 g, 5.37 mmol) and triphenylphosphine (1.41 g, 5.37 mmol) in THF (10.2 mL) was added diisopropyl diazene-1,2-dicarboxylate (1.09 g, 5.37 mmol). The mixture was stirred and heated at 60° C. for 16 h. The solvents were evaporated. The resulting residue was purified by silica gel chromatography with 0-80% EtOAc in hexane to afford a mixture of rac-4-bromo-5-methyl-1-((1-((tetrahydro-2H-pyran-2-yl)oxy)cyclobutyl)methyl)-1H-pyrazole and rac-4-bromo-3-methyl-1-((1-((tetrahydro-2H-pyran-2-yl)oxy)cyclobutyl)methyl)-1H-pyrazole. LCMS (C14H21BrN2O2) (ES, m/z): 329, 331 [M+H]+.
-
- To a stirred solution of 2-(4-bromo-1H-pyrazol-1-yl)cyclopentanol (Intermediate 5) (3.00 g, 13.0 mmol) in DCM (45 mL) was added 3,4-dihydro-2H-pyran (2.4 mL, 26 mmol), followed by 4-methylbenzenesulfonic acid (polymer-bound, 2.0 g). The mixture was stirred at room temperature for 16 h. The mixture was filtered, and the solvents of the filtrate were evaporated. The residue was purified by reversed-phase C18 chromatography with 0-100% MeCN in water as eluent to afford rac-4-bromo-1-(2-((tetrahydro-2H-pyran-2-yl)oxy)cyclopentyl)-1H-pyrazole. LCMS (C13H19BrN2O2) (ES, m/z): 315, 317 [M+H]+.
-
- To a 500 mL round bottom flask was added 4-nitro-1H-pyrazole (15.0 g, 133 mmol), cesium carbonate (64.8 g, 199 mmol), and DMF (195 mL). To the mixture was added 2,2-dimethyloxirane (23.6 mL, 265 mmol). The mixture was heated at 80° C. for 16 h. The mixture was cooled to room temperature. The mixture was filtered and washed with EtOAc. The solvents of the filtrate were evaporated. The resulting residue was purified by silica gel chromatography with 0-80% EtOAc in hexanes, yielding 2-methyl-1-(4-nitro-1H-pyrazol-1-yl)propan-2-ol. LCMS (C7H11N3O3) (ES, m/z): 186 [M+H]+.
-
- To a 500 mL flask was added 2-methyl-1-(4-nitro-1H-pyrazol-1-yl)propan-2-ol (18.8 g, 102 mmol), 10% palladium on carbon (1.08 g, 1.01 mmol), and EtOAc (300 mL). The mixture was degassed under vacuum and refilled with nitrogen three times. The mixture was degassed and refilled with hydrogen from a balloon. The mixture was stirred under an atmosphere of hydrogen for 21 h. The mixture was filtered through Celite® (diatomaceous earth). The solvents of the filtrate were evaporated, yielding 1-(4-amino-1H-pyrazol-1-yl)-2-methylpropan-2-ol. LCMS (C7H13N3O) (ES, m/z): 156 [M+H]+.
-
- To a stirred mixture of 4-nitro-1H-pyrazole (3.00 g, 26.5 mmol) and ethyl 2-bromo-2-methylpropanoate (5.69 g, 29.2 mmol) in DMF (50 mL) was added K2CO3 (11.00 g, 80.00 mmol). The mixture was stirred and heated at 80° C. for 10 h. The mixture was cooled, filtered, and the solvents of the filtrate were evaporated. The resulting residue was purified by silica gel chromatography 5-20% EtOAc in petroleum ether as eluent to afford ethyl 2-methyl-2-(4-nitro-1H-pyrazol-1-yl)propanoate. LCMS (C9H13N3O4) (ES, m/z): 228 [M+H]+.
-
- To a stirred mixture of ethyl 2-methyl-2-(4-nitro-1H-pyrazol-1-yl)propanoate (3.00 g, 13.2 mmol) in EtOH (50 mL) was added NaBH4 (0.999 g, 26.4 mmol). The mixture was stirred at room temperature for 2 h. The mixture was diluted with water (40 mL) and extracted with EtOAc (2×50 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and the solvents of the filtrate were evaporated to afford 2-methyl-2-(4-nitro-1H-pyrazol-1-yl) propan-1-ol.
-
- Step 3 of the synthesis of Intermediate 34 was conducted in a manner similar to that of step 2 of the synthesis of Intermediate 33, using 2-methyl-2-(4-nitro-1H-pyrazol-1-yl) propan-1-ol as the starting material, to afford 2-(4-amino-1H-pyrazol-1-yl)-2-methylpropan-1-ol. LCMS (C7H13N3O) (ES, m/z): 156 [M+H]+.
-
- A solution of 4-fluoro-3-methoxyaniline (350.0 g, 2.48 mol) in EtOAc (3.5 L) was cooled at 0-5° C. To the mixture was added tetra-n-butylammonium tribromide (14.0 kg, 2.90 mol) portionwise. The mixture was warmed to 15° C., and stirred at that temperature for 1 h. The mixture was adjusted to pH 8 with saturated aqueous Na2CO3. The mixture was extracted with EtOAc and the combined organic layers were washed with water (2×1.5 L) and dried with anhydrous Na2SO4. The solids were removed by filtration, and the solvents of the filtrate were evaporated. The resulting residue was purified by silica gel chromatography with 0-100% EtOAc in petroleum ether as eluent to afford 2-bromo-4-fluoro-5-methoxyaniline. LCMS (C7H7BrFNO) (ES, m/z): 220, 222 [M+H]+.
-
- To a solution of 2-bromo-4-fluoro-5-methoxyaniline (300 g, 1.36 mol) in DMF (2.1 L) was added Zn(CN)2 (327 g, 2.78 mol) and Pd(PPh3)4 (90.0 g, 0.0778 mol). The mixture was degassed under vacuum and purged with nitrogen. The mixture was stirred and heated at 130° C. for 1 h under nitrogen. The mixture was poured into ice water (4 L). The mixture was extracted with EtOAc (3 L, 2 L, 1 L), and the combined organic layers were washed with brine (2 L, 1.5 L). The organic layer was dried over anhydrous Na2SO4, filtered, and the solvents of the filtrate were evaporated. The resulting residue was purified by silica gel chromatography with 0-100% EtOAc in petroleum ether as eluent to afford 2-amino-5-fluoro-4-methoxybenzonitrile. LCMS (C8H7FN2O) (ES, m/z): 167 [M+H]+.
-
- To a 20 mL microwave vial was added 2-bromo-5-chloro-4-fluoroaniline (1.00 g, 4.46 mmol), copper(I) cyanide (0.472 g, 4.90 mmol), and NMP (8 mL). The mixture was stirred and heated at 180° C. in a microwave for 1 h. The mixture was diluted in diethyl ether (100 mL) and filtered through Celite® (diatomaceous earth). The filtrate was washed with water (3×100 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered, and the solvents of the filtrate were evaporated, to afford 2-amino-4-chloro-5-fluorobenzonitrile (LCMS (C7H4ClFN2) (ES, m/z): 171 [M+H]+.
-
- To a 20 mL vial was added 2-amino-5-fluoro-4-methoxybenzonitrile (Intermediate 35) (817 mg, 4.92 mmol), DCM (6 mL), and pyridine (1 mL). The mixture was stirred. To the mixture was added 1-(isocyanatomethyl)-2,4-dimethoxybenzene (1425 mg, 7.380 mmol). The mixture was stirred and heated at 40° C. for 16 h. The solids were collected by filtration and washed with MeOH (3×3 mL), to afford 1-(2-cyano-4-fluoro-5-methoxyphenyl)-3-(2,4-dimethoxybenzyl)urea.
-
- To a 100 mL round bottom flask was added 1-(2-cyano-4-fluoro-5-methoxyphenyl)-3-(2,4-dimethoxybenzyl)urea (1.16 g, 3.22 mmol), triphenylphosphine (1.69 g, 6.44 mmol), triethylamine (1.80 ml, 12.9 mmol), and DCM (25 mL). The mixture was stirred and cooled at 0° C. To the mixture was added a solution of carbon tetrabromide (2.14 g, 6.44 mmol) in DCM (5 mL) dropwise. After 30 min, the mixture was concentrated. The resulting residue was purified by silica gel chromatography with 0-70% EtOAc in hexanes as eluent, to afford 2-((((2,4-dimethoxybenzyl)imino)methylene)amino)-5-fluoro-4-methoxybenzonitrile. LCMS (C18H16FN3O3) (ES, m/z) [M+Na]+: 364.
- The intermediates in the following Table 5 were prepared in a manner similar to that of Intermediate 37 from the appropriate intermediates and starting materials.
-
TABLE 5 Ob- served m/z Inter- Structure [M + mediate Name Na]+ 38 364 2-((((2,3-dimethoxybenzyl)imino)methylene)amino)-5- fluoro-3-methoxybenzonitrile 39 368 4-chloro-2-((((2,4- dimethoxybenzyl)imino)methylene)amino)-5- fluorobenzonitrile 40 348 2-((((2,4-dimethoxybenzyl)imino)methylene)amino)-5- fluoro-4-methylbenzonitrile 41 352 2-((((2,4-dimethoxybenzyl)imino)methylene)amino)- 3,5-difluorobenzonitrile 42 384 3,5-dichloro-2-((((2,4- dimethoxybenzyl)imino)methylene)amino)benzonitrile -
- A solution of (R)-ethyl piperidine-3-carboxylate (200.0 g, 1270 mmol), triethylamine (257.5 g, 2540 mmol) and DMAP (15.5 g, 130 mmol) in DCM (2 L) was cooled at 0° C. To the mixture was added di-tert-butyl dicarbonate (305.4 g, 1400 mmol) portionwise. The mixture was stirred at room temperature for 3 h. Then the organic layer was washed with aqueous saturated sodium bicarbonate (3×1 L). The combined organic layers were dried over anhydrous MgSO4, filtered, and the solvents of the filtrate were evaporated to afford 1-(tert-butyl) 3-ethyl (R)-piperidine-1,3-dicarboxylate.
- Intermediate 44 in the following Table 6 was prepared in a manner similar to that of Intermediate 43 from the appropriate starting materials.
-
- To a stirred mixture of 5-methylnicotinic acid (10 g, 72.9 mmol) and concentrated aqueous HCl (0.599 mL, 7.29 mmol) in MeOH (100 mL) at 20° C. was added platinum (IV) oxide (1.67 g, 7.29 mmol). The mixture was degassed and purged with nitrogen then pressurized to 50 psi with hydrogen. The mixture was stirred for 10 h. The mixture was filtered, and the solvents of the filtrate were evaporated to afford the 5-methylpiperidine-3-carboxylic acid.
-
- To a stirred mixture of di-tert-butyl dicarbonate (5.84 ml, 25.1 mmol) and 5-methylpiperidine-3-carboxylic acid (3.00 g, 21.0 mmol) in MeCN (20 mL) and water (20 mL) at 20° C. was added sodium bicarbonate (7.04 g, 84.0 mmol). The mixture was stirred at 20° C. for 5 h. The mixture was diluted with water (20 mL), adjusted with concentrated aqueous HCl to pH 5, and extracted with EtOAc (3×30 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and the solvents of the filtrate were evaporated to afford 1-(tert-butoxycarbonyl)-5-methylpiperidine-3-carboxylic acid. LCMS (C12H21NO4) (ES, m/z) [M+H]+: 244.
-
- To a stirred mixture of 1-(tert-butoxycarbonyl)-5-methylpiperidine-3-carboxylic acid (5.00 g, 20.5 mmol) in DCM (10 mL) and MeOH (10 mL) at 0° C. was added trimethylsilyl-diazomethane (15.4 mL, 30.8 mmol). The mixture was stirred at room temperature for 2 h. The solvents were evaporated to afford 1-tert-butyl 3-methyl 5-methylpiperidine-1,3-dicarboxylate. LCMS (C13H23NO4) (ES, m/z) [M+H]+: 258.
-
- Step 1 of the synthesis of Intermediate 46 was conducted in a manner similar to that of step 1 of the synthesis of Intermediate 45 from the appropriate starting materials to afford methyl 4-methylpiperidine-3-carboxylate. LCMS (C8H15NO2) (ES, m/z) [M+H]+: 158.
-
- Step 2 of the synthesis of Intermediate 46 was conducted in a manner similar to step 2 of the synthesis of Intermediate 45 from the appropriate starting materials, with the exception that the crude material was purified by silica gel chromatography with 0-30% EtOAc in petroleum ether as eluent to afford to 1-(tert-butyl) 3-methyl 4-methylpiperidine-1,4-dicarboxylate. Intermediate 47: mixture of rac,cis-1-(tert-butyl) 3-ethyl-5-fluoropiperidine-1,3-dicarboxylate and rac,trans-1-(tert-butyl) 3-ethyl-5-fluoropiperidine-1,3-dicarboxylate
- To a 250 mL round bottom flask containing rac, cis-1-(tert-butyl) 3-ethyl-5-fluoropiperidine-1,3-dicarboxylate (2.00 g, 7.26 mmol) was added EtOH (73 mL). To the mixture was added sodium tert-butoxide (7.26 mL, 14.5 mmol) (2 M solution in THF) dropwise with stirring. The mixture was stirred at room temperature for 3 h. The mixture was concentrated to about 10 mL of volume. To the mixture was added EtOAc (10 mL). The solvents were evaporated. The residue was dissolved in EtOAc (60 mL) and washed with water (3×20 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvents were evaporated to afford a mixture of rac,cis-1-(tert-butyl) 3-ethyl-5-fluoropiperidine-1,3-dicarboxylate and rac,trans-1-(tert-butyl) 3-ethyl-5-fluoropiperidine-1,3-dicarboxylate.
-
- A 100 mL flask was charged with 1-(4-amino-1H-pyrazol-1-yl)-2-methylpropan-2-ol (4.66 g, 30.0 mmol), methyl 2-methylene-5-oxohexanoate1 (3.12 g, 20.0 mmol), and LiBF4 (1.88 g, 20.0 mmol). To the flask was added TFE (31.2 mL). The flask was fitted with a reflux condenser, which had an inlet for nitrogen. The mixture was heated at reflux for 48 h. The mixture was cooled to room temperature, and to the mixture was added 10% palladium on carbon (0.639 g, 6.00 mmol). The mixture was placed under an atmosphere of hydrogen and stirred at room temperature for 6 h. The mixture was filtered, and the solvents of the filtrate were evaporated. The resulting residue was purified by silica gel chromatography with 0-4% MeOH in DCM as eluent, yielding the racemate with cis relative stereochemistry. The racemic mixture was resolved by chiral SFC (Chiral Technologies AD-H 21×250 mm column with 15% (MeOH w/0.1% NH4OH modifier) as cosolvent), to afford methyl (3S,6R)-1-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-6-methylpiperidine-3-carboxylate (Intermediate 48, first eluting peak) and methyl (3R,6S)-1-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-6-methylpiperidine-3-carboxylate (Intermediate 49, second eluting peak).
- For Intermediate 48: LCMS (C15H25N3O3) (ES, m/z): 296 [M+H]+. For Intermediate 49: LCMS (C15H25N3O3) (ES, m/z): 296 [M+H]+. 1Bizet, V.; Lefebvre, V.; Baudoux, J.; Lasne, M.; Boulange, A.; Leleu, S.; Franck, X.; Rouden, J. Eur. J. Org. Chem. 2011, 4170.
- The intermediates in the following Table 7 were prepared in a manner similar to that of Intermediate 48 and Intermediate 49 from the appropriate intermediates and starting materials, with the exception that these compounds were isolated as racemic mixtures of diastereomers that were not resolved by SFC separation.
-
- A mixture of diethyl malonate (10.0 g, 62.4 mmol), pent-1-en-3-one (5.78 g, 68.7 mmol) and potassium carbonate (0.863 g, 6.24 mmol) was stirred at room temperature in a sealed tube for 3 days. The resulting mixture was filtered to provide the filtrate, which is neat diethyl 2-(3-oxopentyl) malonate. LCMS (C12H20O5) (ES, m/z): 245 [M+H]+. The crude material was used without further purification.
-
- To a stirred solution of 1-(4-amino-1H-pyrazol-1-yl)-2-methylpropan-2-ol (Intermediate 33) (2.00 g, 12.9 mmol) in DCM (129 mL) was added diethyl 2-(3-oxopentyl)malonate (6.93 g, 28.4 mmol) and AcOH (0.077 mL, 1.3 mmol). The mixture was stirred at room temperature for 30 min. To the mixture was added sodium cyanoborohydride (1.62 g, 25.8 mmol) portionwise. The mixture was stirred at room temperature for an additional 30 min. The mixture was quenched with 1 M aqueous HCl (150 mL). The organic layer was separated, and the aqueous layer was extracted with DCM twice more. The combined organic layers were dried over anhydrous Na2SO4, filtered, and the solvents of the filtrate were evaporated to afford rac-diethyl 2-(3-((1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)amino)pentyl)malonate. LCMS (C19H33N3O5) (ES, m/z): 384 [M+H]+.
-
- To a solution of rac-diethyl 2-(3-((1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)amino)pentyl)malonate (1.70 g, 4.43 mmol) in toluene (22 mL) was added AcOH (0.530 mL, 8.87 mmol). The mixture was stirred at 90° C. for 2 days. The mixture was cooled to room temperature, and the solvents were evaporated. The residue was purified by silica gel chromatography with 0-100% EtOAc in hexanes as eluent to afford ethyl 6-ethyl-1-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-2-oxopiperidine-3-carboxylate. LCMS (C17H27N3O4) (ES, m/z): 338 [M+H]+.
-
- To a solution of ethyl 3-oxocyclohexanecarboxylate (2.00 g, 11.7 mmol) in THF (20 mL) was added a solution of sodium borohydride (0.889 g, 23.5 mmol) in THF (10 mL) at 0° C. The mixture was stirred at 0° C. for 2 h. To the mixture was added water (10 mL), and the mixture was extracted with EtOAc (3×15 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and the solvents of the filtrate were evaporated. The resulting residue was purified by silica gel chromatography with 10-50% EtOAc in petroleum ether as eluent to afford ethyl 3-hydroxycyclohexanecarboxylate.
-
- The solution of (R)-1-tert-butyl 3-ethyl piperidine-1,3-dicarboxylate (320.0 g, 1243 mmol) and hydrazine hydrate (311.3 g, 6217 mmol) in EtOH (1.6 L) was stirred and heated at 80° C. for 16 h. The solvents were evaporated. The resulting residue was purified by silica gel chromatography eluting with DCM to afford tert-butyl (R)-3-(hydrazinecarbonyl)piperidine-1-carboxylate. LCMS (C11H21N3O3) (ES, m/z): 244 [M+H]+.
- The intermediates in the following Table 8 were prepared in a manner similar to that of Intermediate 54 from the appropriate intermediates and starting materials.
-
TABLE 8 Structure Observed Intermediate name m/z [M + H]+ 55 258 tert-butyl 3-(hydrazinecarbonyl)azepane-1-carboxylate 56 258 tert-butyl 3-(hydrazinecarbonyl)-5-methylpiperidine-1-carboxylate 57 258 tert-butyl 3-(hydrazinecarbonyl)-4-methylpiperidine-1-carboxylate 58 206 [M + H − C4H8]+ tert-butyl 3-fluoro-4-(hydrazinecarbonyl)piperidine-1-carboxylate 59 206 [M + H − C4H8]+ mixture of tert-butyl (3R,5R and 3S,5S)-3-fluoro-5- (hydrazinecarbonyl)piperidine-1-carboxylate and tert- butyl (3S,5R and 3R,5S)-3-fluoro-5- (hydrazinecarbonyl)piperidine-1-carboxylate 60 248 tert-butyl 3-fluoro-3-(hydrazinecarbonyl)pyrrolidine-1-carboxylate 61 296 (3R,6S)-1-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol- 4-yl)-6-methylpiperidine-3-carbohydrazide 62 296 1-(1-(1-hydroxy-2-methylpropan-2-yl)-1H-pyrazol-4- yl)-6-methylpiperidine-3-carbohydrazide 63 310 1-(1-(2-hydroxy-2-methylpropyl)-3-methyl-1H-pyrazol- 4-yl)-6-methylpiperidine-3-carbohydrazide 64 324 6-ethyl-1-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4- yl)-2-oxopiperidine-3-carbohydrazide 65 159 3-hydroxycyclohexane-1-carbohydrazide 66 258 tert-butyl 5-(hydrazinecarbonyl)-2-methylpiperidine-1-carboxylate -
- A 40 mL reaction vial was charged with ethyl 1-(1-methyl-1H-pyrazol-4-yl)piperidine-3-carboxylate (1.00 g, 6.36 mmol) and THF (15 mL). To the mixture was added 4-bromo-1-methyl-1H-pyrazole (4.96 mL, 48.0 mmol), followed by tBuXPhos-Pd G3 (2.02 g, 2.54 mmol) and sodium tert-butoxide (4.61 g, 48.0 mmol). Nitrogen was bubbled through the mixture for 10 min. The vial was sealed and heated at 65° C. for 24 h. The mixture was cooled to room temperature and diluted with EtOAc (40 mL). The mixture was filtered through Celite® (diatomaceous earth). The solvents of the filtrate were evaporated. The resulting residue was purified by silica gel chromatography with 0-10% MeOH in DCM to afford ethyl 1-(1-methyl-1H-pyrazol-4-yl)piperidine-3-carboxylate. LCMS (C12H19N3O2) (ES, m/z): 238 [M+H]+.
-
- A round bottom flask was charged with ethyl 1-(1-methyl-1H-pyrazol-4-yl)piperidine-3-carboxylate (7.72 g, 32.5 mmol) and EtOH (77 mL). To the mixture was added hydrazine hydrate (31.7 mL, 651 mmol). The round bottom flask was fitted with a reflux condenser, and the mixture was heated at 80° C. for 16 h. The mixture was cooled to room temperature, and the solvents were evaporated to afford (R and S)-1-(1-methyl-1H-pyrazol-4-yl)piperidine-3-carbohydrazide (Intermediate 67). The racemic mixture was resolved by chiral SFC separation (Chiral Technologies AD-H 21×250 mm column with 40% (MeOH w/0.25% DEA modifier) as co-solvent to afford (R or S)-1-(1-methyl-1H-pyrazol-4-yl)piperidine-3-carbohydrazide as the first eluting peak and (S or R)-1-(1-methyl-1H-pyrazol-4-yl)piperidine-3-carbohydrazide as the second eluting peak corresponding to Intermediate 67a and Intermediate 67b, respectively. LCMS (C10H17N5O) (ES, m/z): 224 [M+H]+.
- Intermediate 68 in the following Table 9 was prepared in a manner similar to that of Intermediate 67, with the exception that no SFC separation was conducted. Thus, the compound was isolated as a mixture of isomers.
-
- To a 100 mL round bottom flask was added (R)-1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid (2.00 g, 9.29 mmol) and THF (18.6 mL). To the mixture was added 1,1′-carbonyldiimidazole (1.96 g, 12.1 mmol). The mixture was heated at 60° C. for 30 min. The mixture was cooled to room temperature and transferred to a stirring mixture of hydrazine hydrate (0.447 g, 13.9 mmol) in THF (10 mL) dropwise over 25 min. The mixture was stirred at room temperature for 2 h. The mixture was quenched with water (50 mL) and extracted with EtOAc (2×60 mL). The combined organic layers were dried over anhydrous MgSO4, filtered, and the solvents of the filtrate were evaporated to afford (R)-tert-butyl 3-(hydrazinecarbonyl)pyrrolidine-1-carboxylate. LCMS (C10H19N3O3) (ES, m/z): 230 [M+H]+. The intermediates in the following Table 9A were prepared in a manner similar to that of the preparation of Intermediate 60.
-
TABLE 9A Structure Observed Intermediate Name m/z [M + H]+ 70 186 [M + H − C4H8]+ tert-butyl 1-(hydrazinecarbonyl)-3- azabicyclo[3.1.0]hexane-3-carboxylate 71 158 2-oxopiperidine-3-carbohydrazide 72 268 [M + Na]+ (R)-tert-butyl 2-(hydrazinecarbonyl) morpholine-4-carboxylate 73 316 [M + Na]+ tert-butyl 2-(hydrazinecarbonyl) thiomorpholine-4-carboxylate 1,1-dioxide -
- To a stirred solution of hydrazine hydrate (0.155 mL, 7.11 mmol), 1-((benzyloxy)carbonyl)-3-fluoropiperidine-3-carboxylic acid (2.00 g, 7.11 mmol) and DIPEA (5.02 ml, 28.4 mmol) in DCM (70 mL) was added tripropyl phosphonic anhydride (50% v/v solution in EtOAc, 6.38 mL, 14.2 mmol) dropwise. The mixture was stirred at room temperature for 12 h. The reaction mixture was quenched by adding saturated aqueous sodium bicarbonate. The mixture was stirred for 5 min, the organic layer was separated, dried over anhydrous Na2SO4, filtered, and the solvents of the filtrate were evaporated to afford benzyl 3-fluoro-3-(hydrazinecarbonyl)piperidine-1-carboxylate. LCMS (C14H18FN3O3) (ES, m/z): 296 [M+H]+. Intermediate 75 and Intermediate 76: tert-butyl (2R,5S or 2S,5R)-5-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidine-1-carboxylate and tert-butyl (2S,5R or 2R,5S)-5-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidine-1-carboxylate
- A solution of rac,cis-tert-butyl 5-(hydrazinecarbonyl)-2-methylpiperidine-1-carboxylate (Intermediate 66) (5.00 g, 19.4 mmol) in DCM (7 mL) was added AcOH (0.556 ml, 9.72 mmol). The mixture was stirred at room temperature. To the mixture was added 2-((((2,4-dimethoxybenzyl) imino) methylene) amino)-5-fluoro-4-methoxybenzonitrile (Intermediate 37) (6.63 g, 19.4 mmol). The mixture was stirred for 60 h. The mixture was filtered, and the filtrate was loaded directly onto a silica gel column and purified with 0-100% EtOAc in hexane as eluent to provide the racemic tert-butyl (2R,5S and 2S,5R)-5-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidine-1-carboxylate. The racemic mixture was resolved by chiral SFC (Chiral Technologies AD-H 50×250 mm column, with 35% EtOH as cosolvent) to afford tert-butyl (2R,5S or 2S,5R)-5-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidine-1-carboxylate (Intermediate 75, first eluting peak) and tert-butyl (2S,5R or 2R,5S)-5-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidine-1-carboxylate (Intermediate 76, second eluting peak). The intermediates in the following Table 10 were prepared in a manner similar to Intermediate 75 and Intermediate 76, from the appropriate intermediates and starting materials.
-
TABLE 10 Structure SFC Observed m/z Intermediate Name Conditions [M + H]+ 77 Peak 1; Chiral Technologies AD-H 21 × 25 mm column with 50% (IPA w/ 0.2% DIPA modifier) as co-solvent 565 tert-butyl (1R,5R or 1S,5S)-1-(5-((2,4- dimethoxybenzyl)amino)-9-fluoro-8-methoxy- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)-3- azabicyclo[3.1.0]hexane-3-carboxylate 78 Peak 2; Chiral Technologies AD-H 21 × 250 mm column with 50% (IPA w/ 0.2% DIPA modifier) as co-solvent 565 tert-butyl (1S,5S or 1R,5R)-1-(5-((2,4- dimethoxybenzyl)amino)-9-fluoro-8-methoxy- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)-3- azabicyclo[3.1.0]hexane-3-carboxylate - Intermediates 79-81: tert-butyl (3S,5R or 3R,5S)-3-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-fluoropiperidine-1-carboxylate and tert-butyl (3R,5S or 3S,5R)-3-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-fluoropiperidine-1-carboxylate and tert-butyl (3R,5R and 3S,5S)-3-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-fluoropiperidine-1-carboxylate
- Intermediates 79-81 were prepared from Intermediate 37 and Intermediate 58 in a manner similar to that used for the preparation of Intermediate 75 and Intermediate 76. The crude residue was purified by silica gel chromatography with 0-100% EtOAc in hexane as eluent to afford tert-butyl (3S,5R and 3R,5S)-3-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-fluoropiperidine-1-carboxylate (first eluting peak, mixture of Intermediate 79 and Intermediate 80) and tert-butyl (3R,5R and 3S,5S)-3-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-fluoropiperidine-1-carboxylate (second eluting peak, Intermediate 81). For Intermediate 81: LCMS (C29H34F2N6O5) (ES, m/z): 585 [M+H]+. The mixture of Intermediate 79 and Intermediate 80 was resolved by chiral SFC (Chiral Technologies AD-H 50×250 mm column with 35% MeOH as cosolvent) to afford tert-butyl (3S,5R or 3R,5S)-3-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-fluoropiperidine-1-carboxylate (Intermediate 79, first eluting peak) and tert-butyl (3R,5S or 3S,5R)-3-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-fluoropiperidine-1-carboxylate (Intermediate 80, second eluting peak). For Intermediate 79: LCMS (C29H34F2N6O5) (ES, m/z): 585 [M+H]+. For Intermediate 80: LCMS (C29H34F2N6O5) (ES, m/z): 585 [M+H]+.
-
- To a 40 mL vial was added (R)-tert-butyl 3-(hydrazinecarbonyl)piperidine-1-carboxylate (Intermediate 54) (596 mg, 2.45 mmol), DCM (7 mL) and AcOH (0.070 ml, 1.2 mmol). To the mixture was added 2-((((2,4-dimethoxybenzyl)imino)methylene)amino)-5-fluoro-4-methoxybenzonitrile (Intermediate 37) (836 mg, 2.45 mmol). The mixture was stirred for 16 h. The solution was loaded onto a silica gel column and purified with 0-80% EtOAc in hexane as eluent to afford (R)-tert-butyl 3-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidine-1-carboxylate LCMS (C29H35FN6O5) (ES, m/z) [M+H]+: 567.
-
- To a 20 mL vial was added (R)-tert-butyl 3-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidine-1-carboxylate (1.40 g, 2.47 mmol) and formic acid (4 mL). The solution was stirred for 16 h. The mixture was diluted with DCM (50 mL) and washed with 2 M aqueous potassium carbonate (75 mL). The mixture was extracted with additional DCM (50 mL). The combined organic layers were dried over sodium sulfate, filtered, and the solvents of the filtrate were evaporated to afford (R)—N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-(piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine (Intermediate 82). LCMS (C24H27FN6O3) (ES, m/z) [M+H]+: 467.
- The intermediates in the following Table 11 were synthesized in a manner similar to that used in the preparation of Intermediate 82 from the appropriate intermediates and starting materials. For the synthesis of Intermediate 89, the deprotection step in formic acid (step 2) was not necessary.
-
TABLE 11 Ob- served m/z Inter- Structure [M + mediate Name H]+ 83 481 2-(azepan-3-yl)-N-(2,4-dimethoxybenzyl)-9-fluoro-8- methoxy-[1,2,4]triazolo[1,5-c]quinazolin-5-amine 84 481 2-(azepan-3-yl)-N-(2,4-dimethoxybenzyl)-9-fluoro-7- methoxy-[1,2,4]triazolo[1,5-c]quinazolin-5-amine 85 481 N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-(5- methylpiperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin- 5-amine 86 481 N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-(4- methylpiperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin- 5-amine 87 469 (R)-N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2- (morpholin-2-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5- amine 88 517 2-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8- methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2- yl)thiomorpholine 1,1-dioxide 89 481 3-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8- methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidin- 2-one -
- To a stirred solution of rac-benzyl 3-fluoro-3-(hydrazinecarbonyl)piperidine-1-carboxylate (Intermediate 74) (1.73 g, 5.86 mmol) in DCM (25 mL) was added AcOH (0.201 mL, 3.52 mmol). The mixture was stirred at room temperature for 10 min. To the mixture was added 2-((((2,4-dimethoxybenzyl)imino)methylene)amino)-5-fluoro-3-methoxybenzonitrile (Intermediate 38) (2.00 g, 5.86 mmol). The mixture was stirred and heated at 40° C. for 16 h. The mixture was cooled to room temperature. The mixture was diluted with DCM (100 mL) and then washed with saturated aqueous sodium bicarbonate and brine. The organic layer was dried over anhydrous MgSO4, filtered, and the solvents of the filtrate were evaporated. The resulting residue was purified by silica gel chromatography with EtOAc in isohexane as eluent to afford rac-benzyl 3-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-3-fluoropiperidine-1-carboxylate. LCMS (C32H32F2N6O5) (ES, m/z): 619 [M+H]+.
-
- A 200 mL round bottom flask was charged rac-benzyl 3-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-3-fluoropiperidine-1-carboxylate (2.00 g, 3.23 mmol), 10% Pd/C (800 mg, 3.23 mmol), and MeOH (50 mL). The mixture was stirred under an atmosphere of hydrogen for 16 h. The mixture was filtered through Celite® (diatomaceous earth). and the solvents of the filtrate were evaporated. The residue was purified by silica gel chromatography with 0-8% MeOH in DCM (with 0.2% NH4OH) as eluent to afford a racemic mixture that was resolved by chiral SFC separation (Chiral Technologies, IC 20×250 mm column with 50% (EtOH with 0.2% DEA modifier) as cosolvent) to afford (S or R)—N-(2,4-dimethoxybenzyl)-9-fluoro-2-(3-fluoropiperidin-3-yl)-7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-5-amine (first eluting peak, Intermediate 90) and (R or S)—N-(2,4-dimethoxybenzyl)-9-fluoro-2-(3-fluoropiperidin-3-yl)-7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-5-amine (second eluting peak, Intermediate 91). For Intermediate 90: LCMS (C24H26F2N6O3) (ES, m/z): 485 [M+H]+. For Intermediate 91: LCMS (C24H26F2N6O3) (ES, m/z): 485 [M+H]+.
-
- To a solution of tert-butyl (R)-3-(hydrazinecarbonyl)piperidine-1-carboxylate (Intermediate 54) (1.52 g, 6.25 mmol) in DCM (25 mL) was added AcOH (0.201 mL, 3.52 mmol). The mixture was stirred at room temperature for 10 min. To this mixture was added 2-((((2,4-dimethoxybenzyl)imino)methylene)amino)-5-fluoro-3-methoxybenzonitrile (Intermediate 38) (2.00 g, 5.86 mmol). The mixture was stirred for 16 h. The mixture was diluted with DCM (100 mL), washed with saturated aqueous sodium bicarbonate and brine. The organic layer was dried over anhydrous MgSO4, the solids were removed by filtration, and the solvents of the filtrate were evaporated. The residue was purified by silica gel chromatography with EtOAc in isohexane as eluent to afford tert-butyl (R)-3-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidine-1-carboxylate. LCMS (C29H35FN6O5) (ES, m/z): 567 [M+H]+.
-
- To a solution of tert-butyl (R)-3-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidine-1-carboxylate (2.12 g, 3.74 mmol) in DCM (30 mL) was added 4 M HCl in dioxane (10 mL, 40.0 mmol). The mixture was stirred at room temperature for 2 h. The solvents were evaporated. The residue was purified by silica gel chromatography with 0-8% MeOH in DCM (with 0.2% NH4OH) as eluent to afford (R)—N-(2,4-dimethoxybenzyl)-9-fluoro-7-methoxy-2-(piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine (Intermediate 92). LCMS (C24H27FN6O3) (ES, m/z): 467 [M+H]+.
- The intermediates in the following Table 12 were prepared in a manner similar to that used in the preparation of Intermediate 92 from the appropriate intermediates and starting materials.
- The intermediates in the following Table 12A were prepared in a manner similar to that used in step 2 of the preparation of Intermediate 92 from the appropriate intermediates and starting materials.
-
TABLE 12A Inter- Observed me- Structure m/z diate Name [M + H]+ 95 481 N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2- ((3R,6S or 3S,6R)-6-methylpiperidin-3-yl)- [1,2,4]triazolo[1,5-c]quinazolin-5-amine 96 481 N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2- ((3S,6R or 3R,6S)-6-methylpiperidin-3-yl)- [1,2,4]triazolo[1,5-c]quinazolin-5-amine 97 465 2-((1R,5R or 1S,5S)-3-azabicyclo[3.1.0]hexan- 1-yl)-N-(2,4-dimethoxybenzyl)-9-fluoro-8- methoxy-[1,2,4]triazolo[1,5-c]quinazolin- 5-amine 98 465 2-((1S,5S or 1R,5R)-3-azabicyclo[3.1.0]hexan- 1-yl)-N-(2,4-dimethoxybenzyl)-9-fluoro-8- methoxy-[1,2,4]triazolo[1,5-c]quinazolin- 5-amine 99 485 N-(2,4-dimethoxybenzyl)-9-fluoro-2-((3R,5S or 3S,5R)-5-fluoropiperidin-3-yl)-8-methoxy- [1,2,4]triazolo[1,5-c]quinazolin-5-amine 100 485 N-(2,4-dimethoxybenzyl)-9-fluoro-2-((3S,5R or 3R,5S)-5-fluoropiperidin-3-yl)-8-methoxy- [1,2,4]triazolo[1,5-c]quinazolin-5-amine 101 485 N-(2,4-dimethoxybenzyl)-9-fluoro-2-((3R,5R and 3S,5S)-5-fluoropiperidin-3-yl)-8-methoxy- [1,2,4]triazolo[1,5-c]quinazolin-5-amine 102 485 N-(2,4-dimethoxybenzyl)-9-fluoro-2-((3R,5S and 3S,5R)-5-fluoropiperidin-3-yl)-8-methoxy- [1,2,4]triazolo[1,5-c]quinazolin-5-amine 103 485 N-(2,4-dimethoxybenzyl)-9-fluoro-2-((3R,5R and 3S,5S)-5-fluoropiperidin-3-yl)-8-methoxy- [1,2,4]triazolo[1,5-c]quinazolin-5-amine -
- To a stirred mixture of 2-amino-5-fluoro-3-methoxybenzoic acid (278 mg, 1.50 mmol) in EtOH (1.5 mL) was added cyanamide (158 mg, 3.75 mmol) and hydrochloric acid (325 μL, 1.95 mmol) (6 M, aqueous). The mixture was heated at reflux for 16 h. The mixture was cooled. The precipitate was collected by filtration and dried under high vacuum to afford 2-amino-6-fluoro-8-methoxyquinazolin-4-ol. LCMS (C9H8FN3O2) (ES, m/z): 210 [M+H]+.
-
- POCl3 (295 μL, 3.16 mmol) was added dropwise over 15 min to a stirred mixture of 1,2,4-triazole (524 mg, 7.59 mmol), 2-amino-6-fluoro-8-methoxyquinazolin-4-ol (264.7 mg, 1.265 mmol), and DIPEA (553 μL, 3.16 mmol) in acetonitrile (5 mL) at room temperature. The mixture was stirred and heated at 40° C. for 3 h and then at room temperature for 16 h. The mixture was filtered through Celite® (diatomaceous earth). washing with acetonitrile and diethyl ether to afford 6-fluoro-8-methoxy-4-(1H-1,2,4-triazol-1-yl)quinazolin-2-amine. LCMS (C11H9FN6O) (ES, m/z): 261 [M+H]+.
-
- A 20 mL reaction vial was charged with 6-fluoro-8-methoxy-4-(1H-1,2,4-triazol-1-yl)quinazolin-2-amine (41.1 mg, 0.158 mmol), (R and S)-1-(1-methyl-1H-pyrazol-4-yl)piperidine-3-carbohydrazide Intermediate 67) (38.8 mg, 0.174 mmol), THF (1 mL) and DIPEA (138 μl, 0.790 mmol). The mixture was stirred and heated at 50° C. for 4 h. The mixture was diluted with ethyl acetate (10 mL) and washed with saturated aqueous sodium bicarbonate (20 mL). The organic layer was dried over anhydrous MgSO4, filtered, and the solvents of the filtrate were evaporated to afford rac-N′-(2-amino-6-fluoro-8-methoxyquinazolin-4-yl)-1-(1-methyl-1H-pyrazol-4-yl)piperidine-3-carbohydrazide. LCMS (C19H23 FN8O2) (ES, m/z): 415 [M+H]+.
- The intermediates in the following Table 13 were prepared from the appropriate starting materials in a manner similar to Intermediate 104, with the exception that the enantiopure hydrazide, Intermediate 67b, was used.
-
TABLE 13 Structure Observed Intermediate Name m/z [M + H]+ 105 403 (R os S)-N′-(2-amino-6,7-difluoroquinazolin-4-yl)-1-(1- methyl-1H-pyrazol-4-yl)piperidine-3-carbohydrazide 106 385 (R or S)-N′-(2-amino-6-fluoroquinazolin-4-yl)-1-(1- methyl-1H-pyrazol-4-yl)piperidine-3-carbohydrazide 107 403 (R or S)-N′-(2-amino-6,8-difluoroquinazolin-4-yl)-1-(1- methyl-1H-pyrazol-4-yl)piperidine-3-carbohydrazide 108 403 (R or S)-N′-(2-amino-5,6-difluoroquinazolin-4-yl)-1-(1- methyl-1H-pyrazol-4-yl)piperidine-3-carbohydrazide 109 401 (R or S)-N′-(2-amino-6-chloroquinazolin-4-yl)-1-(1- methyl-1H-pyrazol-4-yl)piperidine-3-carbohydrazide 110 415 (R or S)-N′-(2-amino-6-chloro-8-methylquinazolin-4- yl)-1-(1-methyl-1H-pyrazol-4-yl)piperidine-3- carbohydrazide 111 431 (R or S)-N′-(2-amino-6-chloro-8-methoxyquinazolin-4- yl)-1-(1-methyl-1H-pyrazol-4-yl)piperidine-3- carbohydrazide 112 397 (R or S)-N′-(2-amino-6-methoxyquinazolin-4-yl)-1-(1- methyl-1H-pyrazol-4-yl)piperidine-3-carbohydrazide -
- To a solution of 6-ethyl-1-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-2-oxopiperidine-3-carbohydrazide (Intermediate 64) (270 mg, 0.835 mmol) in dioxane (7 mL) was added AcOH (0.024 mL, 0.42 mmol). The mixture was stirred at room temperature for 30 min. To this mixture was added 2-((((2,4-dimethoxybenzyl)imino)methylene)amino)-5-fluoro-4-methoxybenzonitrile (Intermediate 37) (285 mg, 0.835 mmol). The mixture was stirred at room temperature for 3 days. The mixture was filtered, and the filtrate was purified by silica gel chromatography with 0-100% 3:1 EtOAc:EtOH in hexanes as eluent to afford 3-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-6-ethyl-1-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)piperidin-2-one. LCMS (C33H39FN8O5) (ES, m/z): 647 [M+H]+.
-
- To the solution of 3-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-6-ethyl-1-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)piperidin-2-one (320 mg, 0.495 mmol) in THF (4.9 mL) was added borane in THF (1.0 M, 2.47 mL, 2.47 mmol). The mixture was stirred at room temperature for 24 h. The reaction mixture was quenched with MeOH, and then the solvents were evaporated. The resulting residue was purified by preparative reversed-phase HPLC (Waters SunFire C18 OBD Prep Column, 19 mm×100 mm with MeCN/water (with 0.1% TFA) as eluent) to afford two racemic mixtures of the corresponding diastereomers. Each racemate was resolved by chiral SFC.
- The first eluting racemate was resolved by chiral SFC separation (Chiral Technologies, AS-H, 21×250 mm column with 50% (IPA+0.2% DIPA) as co-solvent) to afford 1-(4-((2R or 2S,5S or 5R)-5-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-ethylpiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol (first eluting peak) and 1-(4-((2S or 2R,5R or 55)-5-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-ethylpiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol (second eluting) corresponding to Intermediate 113 and Intermediate 114, respectively. For Intermediate 113: LCMS (C33H41FN8O4) (ES, m/z): 634 [M+H]+. For Intermediate 114: LCMS (C33H41FN8O4) (ES, m/z): 634 [M+H]+.
- The second eluting racemate was resolved by chiral SFC separation (AS-H, 21×250 mm column with 50% (IPA+0.2% DIPA) as co-solvent) to afford 1-(4-((2S or 2R,5S or 5R)-5-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-ethylpiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol (first eluting peak) and 1-(4-((2R or 2S,5R or 5S)-5-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-ethylpiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol (second eluting peak), corresponding to Intermediate 115 and Intermediate 116, respectively. For Intermediate 115: LCMS (C33H41FN8O4) (ES, m/z): 634 [M+H]+. For Intermediate 116: LCMS (C33H41FN8O4) (ES, m/z): 634 [M+H]+.
-
- A 20 mL microwave vial was charged with (R)—N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-(piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine (Intermediate 82) (500 mg, 1.07 mmol) and THF (6.7 mL). To the mixture was added the mixture of 4-bromo-5-methyl-1-trityl-1H-pyrazole and 4-bromo-3-methyl-1-trityl-1H-pyrazole (Intermediate 16) (865 mg, 2.14 mmol), followed by tBuXPhos-Pd G3 (412 mg, 4.29 mmol) and sodium tert-butoxide (412 mg, 4.29 mmol). Nitrogen was bubbled through the mixture for 10 min. The mixture was stirred and heated at 90° C. for 16 h. The mixture was cooled to room temperature. To the mixture was added Celite® (diatomaceous earth) and saturated aqueous NH4Cl. The mixture was stirred vigorously for 5 min. The mixture was filtered through Celite® (diatomaceous earth) topped with anhydrous MgSO4 and washed with DCM. The solvents of the filtrate were evaporated. The residue was purified by silica gel chromatography with 0-20% MeOH in DCM to afford the mixture of (R)—N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-(1-(5-methyl-1-trityl-1H-pyrazol-4-yl)piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine and (R)—N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-(1-(3-methyl-1-trityl-1H-pyrazol-4-yl)piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine. LCMS (C47H45FN8O3) (ES, m/z): 789 [M+H]+.
-
- To a stirred solution of the mixture of (R)—N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-(1-(3-methyl-1-trityl-1H-pyrazol-4-yl)piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine and (R)—N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-(1-(5-methyl-1H-pyrazol-4-yl)piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine (565 mg, 0.716 mmol) in MeOH (7.2 mL) was added a 4 M solution of HCl in dioxane (1.79 mL, 7.16 mmol). The mixture was stirred at room temperature for 1 h. The solvents were evaporated, and the residue was dissolved in DCM (50 mL). To the mixture was added saturated aqueous sodium bicarbonate (50 mL). The biphasic mixture was separated, and the aqueous layer was extracted with additional DCM (50 mL). The combined organic layers were dried over anhydrous MgSO4, filtered, and the solvents of the filtrate were evaporated to afford the mixture of (R)—N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-(1-(3-methyl-1H-pyrazol-4-yl)piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine and (R)—N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-(1-(5-methyl-1H-pyrazol-4-yl)piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine. LCMS (C28H31FN8O3) (ES, m/z): 547 [M+H]+.
- The intermediates in the following Table 14 were prepared in a manner similar to that used for the preparation of Intermediate 117, from the appropriate starting materials.
-
TABLE 14 Structure Observed Intermediate Name m/z [M + H]+ 118 533 (R)-2-(1-(1H-pyrazol-4-yl)piperidin-3-yl)-N-(2,4- dimethoxybenzyl)-9-fluoro-8-methoxy- [1,2,4]triazolo[1,5-c]quinazolin-5-amine 119 583 (R)-2-(1-(3-(difluoromethyl)-1H-pyrazol-4- yl)piperidin-3-yl)-N-(2,4-dimethoxybenzyl)-9-fluoro- 8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-5-amine -
- To a reaction vial containing of solution of N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-((3R,6S or 3S,6R)-6-methylpiperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine (Intermediate 95) (150 mg, 0.312 mmol) in THF (4 mL) was added 4-bromo-1-(2-((tetrahydro-2H-pyran-2-yl)oxy)cyclopentyl)-1H-pyrazole (Intermediate 32) (177 mg, 0.562 mmol), followed by tBuXPhos-Pd G3 (124 mg, 0.156 mmol) and sodium tert-butoxide (105 mg, 1.09 mmol). The mixture was sparged with nitrogen for 10 min. The mixture was stirred and heated at 90° C. for 16 h. To the mixture was added additional 4-bromo-1-(2-((tetrahydro-2H-pyran-2-yl)oxy)cyclopentyl)-1H-pyrazole (Intermediate 32) (88.5 mg, 0.281 mmol), tBuXPhos-Pd G3 (62 mg, 0.078 mmol) and sodium tert-butoxide (52.5 mg, 0.547 mmol). The mixture was stirred and heated at 90° C. for 16 h. The mixture was purified by preparative silica gel TLC with 4% MeOH in DCM as eluent to afford a mixture of isomers. The mixture was resolved by chiral SFC separation (ID 21×250 mm column with 50% (MeOH w/ACN 1:1+0.2% DIPA) as co-solvent) to afford N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-((3R,6S or 3S,6R)-6-methyl-1-(1-((1R,2R or 1S,2S)-2-((tetrahydro-2H-pyran-2-yl)oxy)cyclopentyl)-1H-pyrazol-4-yl)piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine (first eluting peak, Intermediate 120) and N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-((3R,6S or 3S, 6R)-6-methyl-1-(1-((1S,2S or 1R,2R)-2-((tetrahydro-2H-pyran-2-yl)oxy)cyclopentyl)-1H-pyrazol-4-yl)piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine (fourth eluting peak, Intermediate 121), corresponding to Intermediate 120 and Intermediate 121, respectively. (NOTE: peaks 2 and 3 had poor separation). For Intermediate 120: LCMS (C34H47FN8O5) (ES, m/z): 715 [M+H]+. For Intermediate 121: LCMS (C38H47FN8O5) (ES, m/z): 715 [M+H]+.
-
- To a stirred mixture of sodium tert-butoxide (300 mg, 3.12 mmol), 1-(4-bromo-1H-pyrazol-1-yl)-2-methylpropan-2-ol (Intermediate 4) (274 mg, 1.25 mmol) and N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-(5-methylpiperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine (Intermediate 85) (300 mg, 0.624 mmol) in THF (2 mL) was added tBuXPhos-Pd G3 (149 mg, 0.187 mmol) under a nitrogen atmosphere in a glove box. The mixture was stirred and heated at 100° C. for 14 h. The mixture was purified by preparative silica gel TLC with 10% MeOH in DCM as eluent to afford the two diastereomers: 1-(4-((3R,5S and 3R,5S)-3-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-methylpiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol and 1-(4-((3R,5R and 3S,5S)-3-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-methylpiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol, corresponding to Intermediate 122 and Intermediate 123, respectively. For Intermediate 122, LCMS (C32H39FN8O4) (ES, m/z): 619 [M+H]+. For Intermediate 123, LCMS (C32H39FN8O4) (ES, m/z): 619 [M+H]+.
-
- To a stirred mixture of sodium tert-butoxide (66.5 mg, 0.692 mmol), (R)—N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-(piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine (Intermediate 82) (89.0 mg, 0.190 mmol), 2-(4-bromo-1H-pyrazol-1-yl)-1-methylcyclobutanol (Intermediate 29) (40.0 mg, 0.173 mmol) in THF (2 mL) was added tBuXPhos-Pd G3 (41.3 mg, 0.0520 mmol). The mixture was stirred and heated at 80° C. for 12 h. The mixture was cooled, diluted with EtOAc (10 mL), and washed with water (10 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and the solvents of the filtrate were evaporated. The resulting residue was purified by preparative silica gel TLC with EtOAc as eluent, affording the ring-opened product (R)-5-(4-(3-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidin-1-yl)-1H-pyrazol-1-yl)pentan-2-one. LCMS (C32H37FN8O4) (ES, m/z): 617 [M+H]+.
-
- To a stirred mixture of sodium tert-butoxide (177 mg, 1.84 mmol), (R)—N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-(piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine (Intermediate 82) (236 mg, 0.506 mmol), 4-bromo-1-(2,2-dimethoxycyclobutyl)-1H-pyrazole (Intermediate 30) (120 mg, 0.460 mmol) in THF (4 mL) was added tBuXPhos-Pd G3 (110 mg, 0.138 mmol). The mixture was stirred and heated at 80° C. for 12 h under nitrogen. The mixture was cooled, diluted with EtOAc (10 mL), and then washed with water (10 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and the solvents of the filtrate were evaporated. The residue was purified silica gel chromatography with 0-100% EtOAc in petroleum ether as eluent to afford N-(2,4-dimethoxybenzyl)-2-((3R)-1-(1-(2,2-dimethoxycyclobutyl)-1H-pyrazol-4-yl)piperidin-3-yl)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-5-amine. LCMS (C33H39FN8O5) (ES, m/z): 647 [M+H]+.
-
- A mixture of N-(2,4-dimethoxybenzyl)-2-((3R)-1-(1-(2,2-dimethoxycyclobutyl)-1H-pyrazol-4-yl)piperidin-3-yl)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-5-amine (130 mg, 0.201 mmol) and formic acid (2 mL) was stirred and heated at 40° C. for 15 h. The mixture was cooled and adjusted to pH=8 with saturated aqueous sodium bicarbonate. The mixture was extracted with DCM (3×10 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and the solvents of the filtrate were evaporated. The residue was purified by preparative silica gel TLC with EtOAc as eluent to afford 2-(4-((R)-3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidin-1-yl)-1H-pyrazol-1-yl)cyclobutan-1-one. LCMS (C22H23FN8O2) (ES, m/z): 451 [M+H]+.
-
- To a stirred mixture of 3-hydroxycyclohexanecarbohydrazide (Intermediate 65) (0.556 g, 3.52 mmol) in DCM (30 mL) was added AcOH (0.084 mL, 1.5 mmol). To the solution was added 2-((((2,4-dimethoxybenzyl)imino)methylene)amino)-5-fluoro-4-methoxybenzonitrile (Intermediate 37) (1.00 g, 2.93 mmol). The mixture was stirred and heated at 35° C. for 10 h. The mixture was concentrated. The resulting residue was purified by silica gel chromatography with 10-50% EtOAc in petroleum ether as eluent to afford 3-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)cyclohexanol. LCMS (C25H28FN5O4) (ES, m/z) [M+H]+: 482.
-
- To a stirred solution of 3-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)cyclohexanol (780 mg, 1.62 mmol) in DCM (10 mL) was added DMP (1.37 g, 3.24 mmol) at 0° C. The mixture was warmed to room temperature and stirred for 3 h. The mixture was quenched with saturated aqueous sodium bicarbonate (5 mL), and the mixture was filtered. The filtrate was extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and the solvents of the filtrate were evaporated. The residue was purified by silica gel chromatography with 10-50% EtOAc in petroleum ether to afford 3-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)cyclohexanone. LCMS (C25H26FN5O4) (ES, m/z) [M+H]+: 480.
-
- To a stirred solution of 4-bromo-1-ethyl-1H-pyrazole (621 mg, 3.55 mmol) in THF (3 mL) was added n-butyllithium (1.42 mL, 3.55 mmol, 2.5 M in hexane) at −78° C. The mixture was stirred at −78° C. for 20 min. To the mixture was added a solution of 3-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)cyclohexanone (340 mg, 0.709 mmol) in THF (3 mL) at −78° C., and the mixture was stirred at this temperature for 1 h. The mixture was quenched with saturated aqueous NH4Cl (5 mL) and extracted with EtOAc (3×10 mL). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and the solvents of the filtrate were evaporated. The residue was purified by silica gel chromatography with 10-50% EtOAc in petroleum ether as eluent to afford 3-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-1-(1-ethyl-1H-pyrazol-4-yl). LCMS (C34H34FN7O4) (ES, m/z) [M+H]+: 576.
-
- To a solution of 3-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-1-(1-ethyl-1H-pyrazol-4-yl)cyclohexanol (180 mg, 0.313 mmol) in DCM (4 mL) and water (2 mL) was added DDQ (106 mg, 0.469 mmol) portionwise at 0° C. The mixture was stirred at 0° C. for 30 min. The mixture was diluted with DCM (10 mL) and was washed with Na2SO3 (2 M aqueous solution, 5 mL) and brine (2×10 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and the solvents of the filtrate were evaporated. The residue was purified by reversed-phase HPLC (Waters XBridge C18 OBD Prep Column, 19 mm×100 mm with MeCN/water (w/10 mM NH4HCO3 modifier) as eluent) to afford two diastereomers rac-(1R or 1S,3R or 3S)-3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-1-(1-ethyl-1H-pyrazol-4-yl)cyclohexan-1-ol and rac-(15 or 1R,3S or 3R)-3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-1-(1-ethyl-1H-pyrazol-4-yl)cyclohexan-1-ol, corresponding to Intermediate 126 and Intermediate 127, respectively. For Intermediate 126: LCMS (C21H24FN7O2) (ES, m/z) [M+H]+: 426. For Intermediate 127: LCMS (C21H24FN7O2) (ES, m/z) [M+H]+: 426.
-
- To a mixture of 4-bromo-1H-pyrazole (2.00 g, 13.6 mmol) and cesium carbonate (13.3 g, 40.8 mmol) in MeCN (20 mL) was added cis-2,3-dimethyloxirane (2.38 ml, 27.2 mmol). The mixture was stirred and heated at 80° C. for 16 h. The mixture was cooled to room temperature and the solids were removed by filtration. The filtrate was concentrated, and the residue was diluted with DCM and washed with water and brine solution. The organic layer was dried over anhydrous sodium sulfate. The residue was purified by silica gel chromatography with 0-100% EtOAc in hexanes as eluent to afford (2S,3S and 2R,3R)-3-(4-bromo-1H-pyrazol-1-yl)butan-2-ol. LCMS (C7H11BrN2O) (ES, m/z) [M+H]+: 219, 221.
- The intermediates in the following Table 15 were prepared from the appropriate starting materials in a manner similar to Intermediate 128.
-
TABLE 15 Structure Observed Intermediate Name m/z [M + H]+ 129 219, 221 racemic, anti-3-(4-bromo- 1H-pyrazol-1-yl)butan-2-ol 130 233, 235 racemic, syn-3-(4-bromo-3-methyl- 1H-pyrazol-1-yl)butan-2-ol 131 233, 235 racemic-syn-3-(4-bromo-5-methyl- 1H-pyrazol-1-yl)butan-2-ol 132 186 racemic-syn-3-(4-nitro-1H- pyrazol-1-yl)butan-2-ol 133 202 rac-2-methyl-3-(4-nitro-1H-pyrazol- 1-yl)propane-1,2-diol 134 200 2-methyl-1-(5-methyl-4-nitro- 1H-pyrazol-1-yl)propan-2-ol 135 200 2-methyl-1-(3-methyl-4-nitro- 1H-pyrazol-1-yl)propan-2-ol -
- To a stirred mixture of 4-bromo-1H-pyrazole (0.500 g, 3.40 mmol) in DMF (10 mL) was added K2CO3 (1.18 g, 8.50 mmol) and ethyl 3-bromopropanoate (0.924 g, 5.10 mmol). The mixture was stirred and heated at 60° C. for 8 h. The mixture was diluted with water (30 mL), filtered, and the filtrate was extracted with EtOAc (2×30 mL). The organic layers were dried over anhydrous sodium sulfate, filtered, and the solvents of the filtrate were evaporated. The resulting residue was purified by silica gel column chromatography with 3-25% EtOAc in petroleum ether as eluent to afford ethyl 3-(4-bromo-1H-pyrazol-1-yl)propanoate. LCMS (C8H11BrN2O2) (ES, m/z) [M+H]+: 247, 249.
- The intermediates in the following Table 16 were prepared from the appropriate pyrazole and alkyl halide or mesylate in a manner similar to that used in the preparation of Intermediate 136.
-
TABLE 16 Structure Observed Intermediate Name m/z [M + H]+ 137 231, 233 3-(4-bromo-1H-pyrazol- 1-yl)-3-methylbutan-2-one 138 245, 247 3-(4-bromo-3-methyl-1H-pyrazol- 1-yl)-3-methylbutan-2-one 139 261, 263 methyl 2-(4-bromo-3-methyl- 1H-pyrazol-1-yl)-2-methylpropanoate 140 261, 263 methyl 2-(4-bromo-5-methyl- 1H-pyrazol-1-yl)-2-methylpropanoate 141 203, 205 methyl 2-(4-bromo-5-methyl-1H- pyrazol-1-yl)-2-methylpropanoate 142 307 [M + Na]+ tert-butyl (2-methyl-1-(4-nitro- 1H-pyrazol-1-yl)propan-2-yl)carbamate 143 198 3-methyl-3-(4-nitro-1H-pyrazol- 1-yl)butan-2-one 144 — diethyl 2-methyl-2-(4-nitro-1H- pyrazol-1-yl)malonate -
- To a solution of 1-(4-bromo-1H-pyrazol-1-yl)propan-2-one (Intermediate 141) (2.00 g, 9.85 mmol) in Et2O (22 mL) was added a 3 M solution of ethylmagnesium bromide (9.85 mL, 29.6 mmol) dropwise at 0° C. under a nitrogen atmosphere. The solution was stirred at 0° C. for 1 h, then warmed to room temperature and stirred for 15 h. The mixture was quenched with saturated aqueous ammonium chloride (50 mL), diluted with EtOAc (50 mL) and water (50 mL). The aqueous layer was extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine (2×100 mL), dried over anhydrous Na2SO4, filtered and the solvents were evaporated. The resulting residue was purified by reversed phase HPLC (MeCN/water with 0.05% TFA) to afford rac-1-(4-bromo-1H-pyrazol-1-yl)-2-methylbutan-2-ol. LCMS (C8H13BrN2O) (ES, m/z) [M+H]+: 233, 235.
-
- To a solution of (5-methyl-2-phenyl-1,3-dioxan-5-yl)methanol (4.00 g, 19.2 mmol) in THF (20 mL) was added 4-nitro-1H-pyrazole (2.61 g, 23.1 mmol), triphenylphosphine (10.1 g, 38.4 mmol). To the mixture was slowly added DIAD (5.83 g, 28.8 mmol) in DCM (20 mL). The mixture was stirred at room temperature for 15 h. The solvents were evaporated. The residue was purified by silica gel chromatography with 0-30% EtOAc in petroleum ether to afford 1-((5-methyl-2-phenyl-1,3-dioxan-5-yl)methyl)-4-nitro-1H-pyrazole. LCMS (C15H17N3O4) (ES, m/z) [M+H]+: 304.
- The intermediate in the following Table 17 was prepared from the appropriate pyrazole and alcohol in a manner similar to that described for the synthesis of Intermediate 146.
-
- To a suspension of 3-(4-bromo-3-methyl-1H-pyrazol-1-yl)-3-methylbutan-2-one (Intermediate 138) (1.27 g, 5.18 mmol) in EtOH (25.9 ml) was added sodium borohydride (0.588 g, 15.5 mmol). The mixture was stirred for 16 h. The mixture was diluted with EtOAc (50 mL), washed with water (50 mL) and aqueous potassium hydroxide (1 M, 20 mL). The organic layer was dried over anhydrous MgSO4, filtered, and the solvent of the filtrate was evaporated to afford 3-(4-bromo-3-methyl-1H-pyrazol-1-yl)-3-methylbutan-2-ol, which was taken forward without further purification. LCMS (C9H15BrN2O) (ES, m/z) [M+H]+: 247, 249.
- The intermediates in the following Table 18 were prepared from the appropriate ketone or ester containing pyrazole in a manner similar to that described in the preparation of Intermediate 148.
-
TABLE 18 Observed Inter- Structure m/z mediate Name [M + H]+ 149 233, 235 2-(4-bromo-3-methyl-1H-pyrazol-1-yl)-2- methylpropan-1-ol 150 233, 235 2-(4-bromo-5-methyl-1H-pyrazol-1-yl)-2- methylpropan-1-ol 151 200 rac-3-methyl-3-(4-nitro-1H-pyrazol-1-yl)butan-2-ol 152 202 4-nitro-1-((1-((tetrahydro-2H-pyran-2- yl)oxy)cyclopropyl)methyl)-1H-pyrazole -
- To a solution of ethyl 3-(4-bromo-1H-pyrazol-1-yl)propanoate (100 mg, 0.405 mmol) (Intermediate 136) in THF (4 mL) was added a 3 M solution of MeMgBr in diethyl ether (1.35 mL, 4.05 mmol) at 15° C. under a nitrogen atmosphere. The mixture was stirred at 15° C. for 1 h. The mixture was cooled at 0° C., diluted with water (5 mL), extracted with EtOAc (2×5 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvents of the filtrate were evaporated. The resulting residue was purified by preparative silica gel TLC with 25% EtOAc in petroleum ether as eluent to afford 4-(4-bromo-1H-pyrazol-1-yl)-2-methylbutan-2-ol. LCMS (C8H13BrN2O) (ES, m/z) [M+H]+: 233, 235.
-
- To a solution of Intermediate 129 (9.40 g, 42.9 mmol) in DCM (100 mL) was added 3,4-dihydro-2H-pyran (19.6 mL, 215 mmol) and PPTS (10.8 g, 42.9 mmol). The mixture was stirred at room temperature for 4 h. The mixture was diluted with DCM (15 mL), washed with saturated aqueous NaHCO3 and brine solution. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvents of the filtrate were evaporated. The resulting residue was purified by silica gel chromatography with 0-100% EtOAc in hexanes as eluent to afford rac-4-bromo-1-((2S,3R)-3-((tetrahydro-2H-pyran-2-yl)oxy)butan-2-yl)-1H-pyrazole. LCMS (C12H19BrN2O2) (ES, m/z) [M+H]+: 303, 305.
- The intermediate in the following Table 19 was prepared from the appropriate starting materials in a manner similar to that described for the synthesis of Intermediate 154.
-
- A 100 mL round-bottom flask was charged with 10% Pd/C (200 mg, 0.188 mmol), 3-methyl-3-(4-nitro-1H-pyrazol-1-yl)butan-2-ol (Intermediate 151) (750 mg, 3.76 mmol), and EtOH (31.4 mL). The mixture was degassed by evacuating and backfilling with nitrogen three times. The mixture was then evacuated and refilled with hydrogen from a balloon. The mixture was stirred for 3 h. The mixture was filtered through Celite, and the solvents of the filtrate were evaporated to afford 3-(4-amino-1H-pyrazol-1-yl)-3-methylbutan-2-ol. LCMS (C8H15N3O) (ES, m/z) [M+H]+: 170.
- The intermediates in the following Table 20 were prepared from the appropriate nitro-pyrazole in a manner similar to that described for the preparation of Intermediate 156.
-
TABLE 20 Observed Inter- Structure m/z mediate Name [M + H]+ 157 255 tert-butyl (1-(4-amino-1H-pyrazol-1-yl)-2- methylpropan-2-yl)carbamate 158 — 2-(4-amino-1H-pyrazol-1-yl)-2-methylpropane-1,3-diol 159 172 rac-3-(4-amino-1H-pyrazol-1-yl)-2-methylpropane-1,2- diol 160 156 racemic, syn--3-(4-amino-1H-pyrazol-1-yl)butan-2-ol 161 238 rac-1-((1-((tetrahydro-2H-pyran-2- yl)oxy)cyclopropyl)methyl)-1H-pyrazol-4-amine 162 274 1-((5-methyl-2-phenyl-1,3-dioxan-5-yl)methyl)-1H- pyrazol-4-amine 163 170 1-(4-amino-5-methyl-1H-pyrazol-1-yl)-2-methylpropan- 2-ol 164 170 1-(4-amino-3-methyl-1H-pyrazol-1-yl)-2-methylpropan- 2-ol -
- To a 20 mL vial was added tert-butyl (1-(4-amino-1H-pyrazol-1-yl)-2-methylpropan-2-yl)carbamate (Intermediate 157) (85.0 mg, 0.334 mmol), sodium triacetoxyborohydride (106 mg, 0.501 mmol), and DCE (1.5 mL). The mixture was stirred. To the mixture was added methyl 2-methylene-5-oxohexanoate (0.063 ml, 0.40 mmol). After 20 minutes, to the mixture was added 1 M aqueous KOH (3 mL), water (3 mL), and DCM (3 mL). The organic layer was collected with a phase separator. The solvents were evaporated. To the resulting residue was dissolved in MeOH (1 mL), and water (0.4 mL). The mixture was stirred at room temperature for 72 h. To the mixture was added water (20 mL). The mixture was extracted with DCM (2×20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the solvents were evaporated. The resulting residue was purified by silica gel chromatography with 0-100% EtOAc in hexanes as eluent to afford methyl (3R,6S and 3S,6R)-1-(1-(2-((tert-butoxycarbonyl)amino)-2-methylpropyl)-1H-pyrazol-4-yl)-6-methylpiperidine-3-carboxylate. LCMS (C24H34N4O4) (ES, m/z) [M+H]+: 395.
- To a 20 mL vial was added methyl (3R,6S and 3S,6R)-1-(1-(2-((tert-butoxycarbonyl)amino)-2-methylpropyl)-1H-pyrazol-4-yl)-6-methylpiperidine-3-carboxylate (99.1 mg, 0.251 mmol), EtOH (1 mL), and hydrazine hydrate (0.175 ml, 3.77 mmol). The mixture was heated at 90° C. for 16 h. The solvents were evaporated to afford tert-butyl (1-(4-((2S,5R and 2R,5S)-5-(hydrazinecarbonyl)-2-methylpiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-yl)carbamate. LCMS (C19H34N6O3) (ES, m/z) [M+H]+: 395.
- The intermediates in the following Table 21 were prepared from the appropriate amino-pyrazole in a manner similar to that described for the preparation of Intermediate 165.
-
TABLE 21 Observed Inter- Structure m/z mediate Name [M + H]+ 166 312 1-(1-(1,3-dihydroxy-2-methylpropan-2-yl)-1H-pyrazol- 4-yl)-6-methylpiperidine-3-carbohydrazide 167 312 1-(1-(2,3-dihydroxy-2-methylpropyl)-1H-pyrazol-4-yl)- 6-methylpiperidine-3-carbohydrazide 168 414 6-methyl-1-(1-((5-methyl-2-phenyl-1,3-dioxan-5- yl)methyl)-1H-pyrazol-4-yl)piperidine-3- carbohydrazide 169 378 6-methyl-1-(1-((1-((tetrahydro-2H-pyran-2- yl)oxy)cyclopropyl)methyl)-1H-pyrazol-4-yl)piperidine- 3-carbohydrazide 170 224 (3R,6S and 3S,6R)-6-methyl-1-(1H-pyrazol-4- yl)piperidine-3-carbohydrazide -
- A solution of methyl 2-(bromomethyl)acrylate (6.04 ml, 50.3 mmol) and DMAP (6.76 g, 55.3 mmol) in DCM (201 mL) was stirred at room temperature for 30 minutes. To the mixture were added propionaldehyde (5.41 ml, 75 mmol) and L-proline (5.79 g, 50.3 mmol). The mixture was stirred at 23° C. for 48 hours. The mixture was washed with water (200 mL), 1 M aqueous HCl (100 mL), and brine (100 mL). The organic layer was dried over anhydrous MgSO4, filtered, and the solvents were evaporated. The resulting residue was purified by silica gel chromatography with 0-2.5% MeOH in DCM as eluent to afford methyl 4-methyl-2-methylene-5-oxopentanoate.
- 1-(4-amino-5-methyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol (Intermediate 163) (1.43 g, 8.45 mmol) was dissolved in MeOH (25.6 mL). To the mixture was added sodium triacetoxyborohydride (6.51 g, 30.7 mmol), followed by methyl 4-methyl-2-methylene-5-oxopentanoate (1.20 mL, 7.68 mmol). The mixture was stirred for 5 min (until the sodium triacetoxyborohydride went into solution). The mixture was quenched with 1 M aqueous sodium hydroxide (30.7 mL, 30.7 mmol) and allowed to stir for 48 h. The MeOH was evaporated, and to the mixture was added DCM (30 mL). The layers were separated and the DCM layer was dried with anhydrous MgSO4, filtered, and the solvents of the filtrate were evaporated. The residue was purified by silica gel chromatography with 0-10% MeOH in DCM to afford methyl (3R,5R and 3S,5S)-1-(1-(2-hydroxy-2-methylpropyl)-5-methyl-1H-pyrazol-4-yl)-5-methylpiperidine-3-carboxylate. LCMS (C16H27N3O3) (ES, m/z) [M+H]+: 310.
- Methyl (3R,5R and 3S,5S)-1-(1-(2-hydroxy-2-methylpropyl)-5-methyl-1H-pyrazol-4-yl)-5-methylpiperidine-3-carboxylate (1.39 g, 4.49 mmol) was stirred in MeOH (35.9 ml) with potassium tert-butoxide (1.01 g, 8.98 mmol) for 18 h at 60° C. The mixture was cooled to room temperature, and the solvents were evaporated. The resulting residue was dissolved in DCM and quenched with saturated aqueous NH4Cl. The layers were separated using a Biotage Isolute® phase separator and the DCM layer was concentrated. The resulting residue was purified by silica gel chromatography with 0-10% MeOH in DCM to afford a mixture of methyl (3S,5R and 3R,5S)-1-(1-(2-hydroxy-2-methylpropyl)-5-methyl-1H-pyrazol-4-yl)-5-methylpiperidine-3-carboxylate and methyl (3R,5R and 3S,5S)-1-(1-(2-hydroxy-2-methylpropyl)-5-methyl-1H-pyrazol-4-yl)-5-methylpiperidine-3-carboxylate. LCMS (C16H27N3O3) (ES, m/z) [M+H]+: 310.
- To a solution of the product from step 3 (1.18 g, 3.81 mmol) in ethanol (15.3 mL) was added hydrazine hydrate (1.87 mL, 38.1 mmol). The mixture was stirred and heated at 80° C. for 16 h. The mixture was cooled to room temperature and the solvents were evaporated to afford (3R,5S and 3S,5R)-1-(1-(2-hydroxy-2-methylpropyl)-5-methyl-1H-pyrazol-4-yl)-5-methylpiperidine-3-carbohydrazide and (3R,5R and 3S,5S)-1-(1-(2-hydroxy-2-methylpropyl)-5-methyl-1H-pyrazol-4-yl)-5-methylpiperidine-3-carbohydrazide LCMS (C15H27N5O2) (ES, m/z) [M+H]+: 310.
-
- N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-(5-methylpiperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine (Intermediate 85) (2.52 g, 5.24 mmol) was subjected to chiral SFC separation (Phenomenex Lux-3 21×250 mm column with 20% MeOH (w/0.1% NH4OH) as cosolvent) to afford rac-N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-((3R,5S)-5-methylpiperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine (combination of peaks 2 and 3) and rac-N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-((3S,5S)-5-methylpiperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine (combination of peaks 1 and 4). LCMS (C25H29FN6O3) (ES, m/z) [M+H]+: 481.
-
- To a 100 mL round bottom flask was added tert-butyl 3-(hydrazinecarbonyl)-5-methylpiperidine-1-carboxylate (Intermediate 56) (1.56 g, 6.07 mmol), 1,4-dioxane (20 mL), and acetic acid (0.174 mL, 3.04 mmol). The mixture was stirred. To this stirring mixture was added 2-((((2,4-dimethoxybenzyl)imino)methylene)amino)-3,5-difluorobenzonitrile (Intermediate 41) (2.00 g, 6.07 mmol). The mixture was stirred at 75° C. for 16 h. The mixture was purified by silica gel chromatography with 0-50% EtOAc in hexanes as eluent to afford tert-butyl (3R,5S and 3S,5R)-3-(5-((2,4-dimethoxybenzyl)amino)-7,9-difluoro-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-methylpiperidine-1-carboxylate (first eluting) and tert-butyl (3S,5S and 3R,5R)-3-(5-((2,4-dimethoxybenzyl)amino)-7,9-difluoro-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-methylpiperidine-1-carboxylate (second eluting). LCMS (C29H34F2N6O4) (ES, m/z) [M+H]+: 569.
- tert-butyl (3R,5S and 3S,5R)-3-(5-((2,4-dimethoxybenzyl)amino)-7,9-difluoro-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-methylpiperidine-1-carboxylate and tert-butyl (3S,5S and 3R,5R)-3-(5-((2,4-dimethoxybenzyl)amino)-7,9-difluoro-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-methylpiperidine-1-carboxylate from Step 1 were converted to N-(2,4-dimethoxybenzyl)-7,9-difluoro-2-((3R,5S and 3S,5R)-5-methylpiperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine (Intermediate 174) and N-(2,4-dimethoxybenzyl)-7,9-difluoro-2-((3S,5S and 3R,5R)-5-methylpiperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine (Intermediate 175) (LCMS (C24H26F2N6O2) (ES, m/z) [M+H]+: 469) with formic acid in a manner similar to the synthesis of Intermediate 82.
- The intermediates in the following Table 22 were prepared in a similar manner to that described for the synthesis of Intermediate 174 from the appropriate hydrazide and carbodiimide.
-
TABLE 22 Observed Inter- Structure m/z mediate Name [M + H]+ 176 481 N-(2,4-dimethoxybenzyl)-9-fluoro-7-methoxy-2- ((3R,5S and 3S,5R)-5-methylpiperidin-3-yl)- [1,2,4]triazolo[1,5-c]quinazolin-5-amine 177 547 N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2- ((3R,6S and 3S,6R)-6-methyl-1-(1H-pyrazol-4- yl)piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5- amine -
- To a mixture of 2-bromo-5-(difluoromethoxy)-4-fluoroaniline (1.40 g, 5.47 mmol) and zinc cyanide (1.28 g, 10.9 mmol) in NMP (4 mL) was added bis(tri-tert-butylphosphine)palladium(0) (0.699 g, 1.37 mmol). The mixture was stirred and heated at 160° C. under nitrogen for 1 h in a microwave reactor. The mixture was cooled to room temperature. To the mixture was added brine (60 mL), and the mixture was extracted with petroleum ether:ethyl acetate (3:1) (3×25 mL), the combined organic layers were dried over anhydrous Na2SO4, filtered, and the solvents of the filtrate were evaporated. The resulting residue was purified by silica gel chromatography with 25% EtOAc in petroleum ether to afford 2-amino-4-(difluoromethoxy)-5-fluorobenzonitrile.
-
- A solution of 2-amino-4-(difluoromethoxy)-5-fluorobenzonitrile (500 mg, 2.47 mmol) in methyl carbonochloridate (3.04 g, 32.2 mmol) was stirred and heated at 75° C. under a nitrogen atmosphere for 15 h. The mixture was cooled, diluted with water (10 mL), extracted with EtOAc (3×20 mL), dried over anhydrous Na2SO4, filtered, and the solvents of the filtrate were evaporated. The residue was purified by silica gel chromatography to afford methyl (2-cyano-5-(difluoromethoxy)-4-fluorophenyl)carbamate.
-
- To a solution of methyl (2-cyano-5-(difluoromethoxy)-4-fluorophenyl)carbamate (400 mg, 1.537 mmol) in NMP (4 mL) was added (R)-tert-butyl 3-(hydrazinecarbonyl)piperidine-1-carboxylate (411 mg, 1.691 mmol) (Intermediate 54). The mixture was stirred and heated at 170° C. for 30 min. The mixture was cooled, diluted with water (30 mL) and extracted with EtOAc (3×30 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and the solvents of the filtrate were evaporated. The resulting residue was purified by silica gel chromatography with 0-30% EtOAc in hexanes as eluent to afford (R)-tert-butyl-3-(8-(difluoromethoxy)-9-fluoro-5-hydroxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidine-1-carboxylate. LCMS (C24H22F3N5O4) (ES, m/z) [M+H]+: 454.
-
- To a solution of tert-butyl-3-(8-(difluoromethoxy)-9-fluoro-5-hydroxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidine-1-carboxylate (1.00 g, 2.21 mmol) in MeCN (10 mL) was added DBU (0.831 mL, 5.51 mmol), PyBroP (1.34 g, 2.87 mmol) and (2,4-dimethoxyphenyl)methanamine (0.553 g, 3.31 mmol) at 90° C. under a nitrogen atmosphere. The mixture was stirred at 90° C. for 12 h. The solvents were evaporated. The resulting residue was purified by silica gel chromatography with 0-50% EtOAc in hexanes as eluent to afford tert-butyl-3-(8-(difluoromethoxy)-5-((2,4-dimethoxybenzyl)amino)-9-fluoro-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidine-1-carboxylate. LCMS (C29H33F3N6O5) (ES, m/z) [M+H]+: 603.
-
- To a solution of tert-butyl-3-(8-(difluoromethoxy)-5-((2,4-dimethoxybenzyl)amino)-9-fluoro-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidine-1-carboxylate (700 mg, 1.16 mmol) in DCM (7 mL) was added TFA (0.7 mL) at 15° C. under a nitrogen atmosphere. The mixture was stirred at 15° C. for 2 h. The mixture was cooled, diluted with NaHCO3 (15 mL), extracted with DCM (3×20 mL), dried over anhydrous Na2SO4, and the solvents were evaporated. The resulting residue was purified by silica gel chromatography with 0-50% EtOAc in petroleum ether as eluent to afford (R)-8-(difluoromethoxy)-N-(2,4-dimethoxybenzyl)-9-fluoro-2-(piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine. LCMS (C24H25F3N6O3) (ES, m/z) [M+H]+: 503.
-
- A 5 mL microwave vial was charged with (R)—N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-(piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine (Intermediate 82) (100 mg, 0.214 mmol), tBuXPhos-Pd G3 (68.1 mg, 0.086 mmol) and sodium tert-butoxide (82 mg, 0.86 mmol). To the mixture was added 1-(3-bromo-1H-1,2,4-triazol-1-yl)-2-methylpropan-2-ol (Intermediate 2) (94 mg, 0.429 mmol) in THF (1.4 mL). The mixture was sparged with nitrogen for 10 min. The mixture was stirred and heated at 90° C. for 16 h. The mixture was cooled to room temperature, and the solids were removed by filtration and washed with DCM. The solvents of the filtrate were evaporated. To the resulting residue was added TFA (0.5 mL). The mixture was stirred and heated at 50° C. for 3 h. The mixture was cooled to room temperature, and the solvents were evaporated. The residue was purified by preparative reversed-phase HPLC (Waters SunFire C18 OBD Prep Column, 19 mm×100 mm MeCN/H2O with 0.1% TFA as eluent) to afford (R)-1-(3-(3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidin-1-yl)-1H-1,2,4-triazol-1-yl)-2-methylpropan-2-ol. LCMS (C21H26FN9O2) (ES, m/z): 458 [M+H]+. 1H NMR (499 MHz, DMSO-d6) δ 8.17 (s, 1H), 7.89 (d, J=10.9 Hz, 1H), 7.81 (s, 2H), 7.19 (d, J=7.9 Hz, 1H), 4.31 (d, J=12.8 Hz, 1H), 3.97 (s, 4H), 3.91 (s, 2H), 3.15 (ddt, J=10.9, 6.7, 3.4 Hz, 1H), 3.11-3.04 (m, 1H), 2.86 (td, J=12.5, 2.7 Hz, 1H), 2.23 (d, J=12.1 Hz, 1H), 1.92-1.77 (m, 2H), 1.75-1.63 (m, 1H), 1.10 (d, J=2.4 Hz, 6H).
- The example compounds of the invention in the following Table 15 were prepared in a manner similar to that described in Example 1, from the appropriate starting aryl halide and amine intermediates.
-
TABLE 15 Structure Observed Example Name m/z [M + H]+ 2 397 (R)-9-fluoro-8-methoxy-2-(1-(1-methyl-1H-pyrazol-4- yl)piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine 3 439 (R)-2-(1-(1-(tert-butyl)-1H-pyrazol-4-yl)piperidin-3-yl)-9- fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-5-amine 4 425 (R)-9-fluoro-2-(1-(1-isopropyl-1H-pyrazol-4-yl)piperidin-3-yl)- 8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-5-amine 5 465 (R)-9-fluoro-8-methoxy-2-(1-(1-(2,2,2-trifluoroethyl)-1H- pyrazol-4-yl)piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5- amine 6 398 (R)-9-fluoro-8-methoxy-2-(1-(1-methyl-1H-1,2,3-triazol-4- yl)piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine 7 455 (R)-1-(4-(3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5- c]quinazolin-2-yl)piperidin-1-yl)-1H-pyrazol-1-yl)-2- methylpropan-2-ol 8 469 (R)-1-(4-(3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5- c]quinazolin-2-yl)piperidin-1-yl)-5-methyl-1H-pyrazol-1-yl)-2- methylpropan-2-ol 9 469 (R)-1-(4-(3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5- c]quinazolin-2-yl)piperidin-1-yl)-3-methyl-1H-pyrazol-1-yl)-2- methylpropan-2-ol 10 467 (R)-1-((4-(3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5- c]quinazolin-2-yl)piperidin-1-yl)-1H-pyrazol-1- yl)methyl)cyclobutan-1-ol 11 469 (R)-2-(4-(3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5- c]quinazolin-2-yl)piperidin-1-yl)-3-methyl-1H-pyrazol-1-yl)-2- methylpropan-1-ol 12 469 (from Intermediate 26) (S or R)-3-(4-((R)-3-(5-amino-9-fluoro-8-methoxy- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidin-1-yl)-1H- pyrazol-1-yl)-2-methylbutan-2-ol 13 469 (from Intermediate 27) (R or S)-3-(4-((R)-3-(5-amino-9-fluoro-8-methoxy- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidin-1-yl)-1H- pyrazol-1-yl)-2-methylbutan-2-ol 14 467 (1s,3s)-3-(4-((R)-3-(5-amino-9-fluoro-8-methoxy- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidin-1-yl)-1H- pyrazol-1-yl)-1-methylcyclobutan-1-ol 15 467 (R)-9-fluoro-8-methoxy-2-(1-(1-((3-methyloxetan-3- yl)methyl)-1H-pyrazol-4-yl)piperidin-3-yl)-[1,2,4]triazolo[1,5- c]quinazolin-5-amine 16 481 (R)-9-fluoro-8-methoxy-2-(1-(5-methyl-1-(tetrahydro-2H- pyran-4-yl)-1H-pyrazol-4-yl)piperidin-3-yl)-[1,2,4]triazolo[1,5- c]quinazolin-5-amine 17 481 (R)-9-fluoro-8-methoxy-2-(1-(3-methyl-1-(tetrahydro-2H- pyran-4-yl)-1H-pyrazol-4-yl)piperidin-3-yl)-[1,2,4]triazolo[1,5- c]quinazolin-5-amine 18 517 (R)-2-(1-(5-(difluoromethyl)-1-(tetrahydro-2H-pyran-4-yl)-1H- pyrazol-4-yl)piperidin-3-yl)-9-fluoro-8-methoxy- [1,2,4]triazolo[1,5-c]quinazolin-5-amine 19 517 (R)-2-(1-(3-(difluoromethyl)-1-(tetrahydro-2H-pyran-4-yl)-1H- pyrazol-4-yl)piperidin-3-yl)-9-fluoro-8-methoxy- [1,2,4]triazolo[1,5-c]quinazolin-5-amine 20 441 (R)-(4-(3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5- c]quinazolin-2-yl)piperidin-1-yl)-1-ethyl-1H-pyrazol-3- yl)methanol 21 495 (R)-1-(4-(3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5- c]quinazolin-2-yl)piperidin-1-yl)-3-cyclopropyl-1H-pyrazol-1- yl)-2-methylpropan-2-ol 22 460 (R)-2-(1-(6-(difluoromethoxy)pyridin-3-yl)piperidin-3-yl)-9- fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-5-amine 23 452 (R)-9-fluoro-2-(1-(6-isopropoxypyridin-3-yl)piperidin-3-yl)-8- methoxy-[1,2,4]triazolo[1,5-c]quinazolin-5-amine 24 474 (R)-2-(1-(6-(difluoromethoxy)-5-methylpyridin-3-yl)piperidin- 3-yl)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-5- amine 25 474 (R)-5-(3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5- c]quinazolin-2-yl)piperidin-1-yl)-1-(difluoromethyl)-3- methylpyridin-2(1H)-one 26 424 (R)-9-fluoro-8-methoxy-2-(1-(6-methoxypyridin-3-yl)piperidin- 3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine 27 470 (R)-1-(3-(3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5- c]quinazolin-2-yl)piperidin-1-yl)-5-methyl-1H-1,2,4-triazol-1- yl)-2-methylpropan-2-ol 28 455 (R)-1-(4-(3-(5-amino-9-fluoro-7-methoxy-[1,2,4]triazolo[1,5- c]quinazolin-2-yl)piperidin-1-yl)-1H-pyrazol-1-yl)-2- methylpropan-2-ol 29 469 (R)-1-(4-(3-(5-amino-9-fluoro-7-methoxy-[1,2,4]triazolo[1,5- c]quinazolin-2-yl)piperidin-1-yl)-5-methyl-1H-pyrazol-1-yl)-2- methylpropan-2-ol 30 469 (R)-1-(4-(3-(5-amino-9-fluoro-7-methoxy-[1,2,4]triazolo[1,5- c]quinazolin-2-yl)piperidin-1-yl)-3-methyl-1H-pyrazol-1-yl)-2- methylpropan-2-ol 31 467 (R)-1-((4-(3-(5-amino-9-fluoro-7-methoxy-[1,2,4]triazolo[1,5- c]quinazolin-2-yl)piperidin-1-yl)-1H-pyrazol-1- yl)methyl)cyclobutan-1-ol 32 455 (R)-2-(4-(3-(5-amino-9-fluoro-7-methoxy-[1,2,4]triazolo[1,5- c]quinazolin-2-yl)piperidin-1-yl)-1H-pyrazol-1-yl)-2- methylpropan-1-ol 33 460 (R)-2-(1-(6-(difluoromethoxy)pyridin-3-yl)piperidin-3-yl)-9- fluoro-7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-5-amine 34 424 (R)-9-fluoro-7-methoxy-2-(1-(6-methoxypyridin-3-yl)piperidin- 3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine 35 452 (R)-9-fluoro-2-(1-(6-isopropoxypyridin-3-yl)piperidin-3-yl)-7- methoxy-[1,2,4]triazolo[1,5-c]quinazolin-5-amine 36 456 (R)-1-(3-(3-(5-amino-9-fluoro-7-methoxy-[1,2,4]triazolo[1,5- c]quinazolin-2-yl)piperidin-1-yl)-1H-1,2,4-triazol-1-yl)-2- methylpropan-2-ol 37 470 (R)-1-(3-(3-(5-amino-9-fluoro-7-methoxy-[1,2,4]triazolo[1,5- c]quinazolin-2-yl)piperidin-1-yl)-5-methyl-1H-1,2,4-triazol-1- yl)-2-methylpropan-2-ol 38 453 (R)-1-((4-(3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5- c]quinazolin-2-yl)pyrrolidin-1-yl)-1H-pyrazol-1- yl)methyl)cyclobutan-1-ol 39 469 rac-1-(4-(3-(5-amino-9-fluoro-7-methoxy-[1,2,4]triazolo[1,5- c]quinazolin-2-yl)azepan-1-yl)-1H-pyrazol-1-yl)-2- methylpropan-2-ol -
- To a reaction vial containing of solution of N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-((3R,6S or 3S,6R)-6-methylpiperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine (Intermediate 95) (600 mg, 1.25 mmol) in THF (12 ml) was added rac-4-bromo-1-((1-((tetrahydro-2H-pyran-2-yl)oxy)cyclobutyl)methyl)-1H-pyrazole (Intermediate 23) (590 mg, 1.87 mmol) followed by tBuXPhos-Pd G3 (298 mg, 0.375 mmol) and sodium tert-butoxide (420 mg, 4.37 mmol). Nitrogen was bubbled through the mixture for 10 min. The mixture was stirred and heated at 90° C. for 4 h. The mixture was cooled to room temperature. To the mixture was added additional tBuXPhos-Pd G3 (149 mg, 0.188 mmol) followed by sodium tert-butoxide (210 mg, 2.19 mmol). Nitrogen was bubbled through the mixture for an additional 10 min. The mixture was stirred and heated at 90° C. for 18 h. The mixture was cooled to room temperature, and then the solvents were evaporated. The residue was partitioned between DCM and water. The organic layer was washed with brine, dried over anhydrous MgSO4, and the solids were removed by filtration. The filtrate was concentrated. The resulting residue was purified by silica gel chromatography with 0-40% EtOAc:EtOH (3:1) in hexane as eluent. The obtained residue was further purified by preparative silica gel TLC with 4% MeOH in DCM as eluent to afford N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-((3R,6S or 3S,6R)-6-methyl-1-(1-((1-(((RS)-tetrahydro-2H-pyran-2-yl)oxy)cyclobutyl)methyl)-1H-pyrazol-4-yl)piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine. LCMS (C38H47FN8O5) (ES, m/z): 715 [M+H]+.
-
- To a reaction vial was added N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-((3R,6S or 3S,6R)-6-methyl-1-(1-((1-(((RS)-tetrahydro-2H-pyran-2-yl)oxy)cyclobutyl)methyl)-1H-pyrazol-4-yl)piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine (1.40 g, 2.22 mmol) and TFA (1.65 mL, 22.2 mmol). The mixture was stirred and heated at 60° C. for 1 h. The mixture was cooled to room temperature, and then the solvents were evaporated. The residue was purified by silica gel chromatography with 6% (7 M ammonia solution in MeOH) in DCM as eluent to afford 1-((4-((2S,5R or 2R,5S)-5-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-1H-pyrazol-1-yl)methyl)cyclobutan-1-ol (Example 40). LCMS (C24H29FN8O2) (ES, m/z): 481 [M+H]+. 1H NMR (500 MHz, Methanol-d4) δ 7.87 (d, J=10.9 Hz, 1H), 7.35 (s, 1H), 7.27 (s, 1H), 7.15 (d, J=7.6 Hz, 1H), 4.14 (s, 2H), 3.99 (s, 3H), 3.73 (d, J=4.9 Hz, 1H), 3.47 (d, J=9.2 Hz, 1H), 3.36-3.20 (m, 3H), 2.11 (d, J=7.9 Hz, 3H), 2.02 (p, J=10.7, 9.6 Hz, 2H), 1.89-1.69 (m, 2H), 1.55 (dq, J=19.0, 9.6 Hz, 1H), 1.37-1.20 (m, 2H), 1.12 (d, J=6.6 Hz, 3H), 0.96-0.82 (m, 2H).
- The example compounds of the invention in the following Table 16 were prepared in a manner similar to that described for the preparation of Example 40 from the appropriate starting aryl halide and Intermediate 95.
-
TABLE 16 Structure Observed m/z Example Name [M + H]+ 41 483 1-(4-((2S,5R or 2R,5S)-5-(5-amino-9-fluoro-8-methoxy- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1- yl)-5-methyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol 42 483 1-(4-((2S,5R or 2R,5S)-5-(5-amino-9-fluoro-8-methoxy- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1- yl)-3-methyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol 43 497 3-(4-((2S,5R or 2R,5S)-5-(5-amino-9-fluoro-8-methoxy- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1- yl)-1H-pyrazol-1-yl)-2,3-dimethylbutan-2-ol 44 481 9-fluoro-8-methoxy-2-((3R,6S or 3S,6R)-6-methyl-1-(1- (tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)piperidin-3-yl)- [1,2,4]triazolo[1,5-c]quinazolin-5-amine 45 495 9-fluoro-8-methoxy-2-((3R,6S or 3S,6R)-6-methyl-1-(5- methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4- yl)piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine 46 495 9-fluoro-8-methoxy-2-((3R,6S or 3S,6R)-6-methyl-1-(3- methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4- yl)piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine 47 499 9-fluoro-2-((3R,6S or 3S,6R)-1-(1-((3-(fluoromethyl)oxetan- 3-yl)methyl)-1H-pyrazol-4-yl)-6-methylpiperidin-3-yl)-8- methoxy-[1,2,4]triazolo[1,5-c]quinazolin-5-amine -
- Step 1 of the synthesis of Example 48 and Example 49 was conducted with Intermediate 95 and Intermediate 1 in a manner similar to that described in step 1 of the synthesis of Example 40. The resulting diastereomeric mixture was purified by SFC (Chiral Technologies AD-H 21×250 mm column with 55% (IPA+0.2% DIPA) as co-solvent), to afford peak 1 and peak 2 corresponding to (R or S)-3-(4-((2S,5R or 2R,5S)-5-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylbutan-2-ol and (S or R)-3-(4-((2S,5R or 2R,5S)-5-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylbutan-2-ol. For peak 1, LCMS (C33H41FN8O4) (ES, m/z): 633 [M+H]+. For peak 2, LCMS (C33H41FN8O4) (ES, m/z): 633 [M+H]+.
-
- Step 2 of the synthesis of Example 48 and Example 49 was conducted in a manner similar to that described in step 2 of Example 40, where peak 1 was converted to (R or S)-3-(4-((2S,5R or 2R,5S)-5-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylbutan-2-ol (Example 48) and peak 2 was converted to (S or R)-3-(4-((2S,5R or 2R,5S)-5-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylbutan-2-ol (Example 49).
- For Example 48: LCMS (C24H31FN8O2) (ES, m/z): 483 [M+H]+. 1H NMR (400 MHz, Chloroform-d) δ 7.99 (d, J=10.7 Hz, 1H), 7.26 (s, 1H), 7.15 (d, J=7.6 Hz, 1H), 7.01 (s, 1H), 5.74 (s, 2H), 4.14 (s, 1H), 4.02 (m, 1H), 4.00 (s, 3H), 3.74 (m, 1H), 3.49 (s, 1H), 3.45 (dd, J=11.6, 3.8 Hz, 1H), 3.32 (dd, J=11.3, 4.0 Hz, 1H), 3.20 (t, J=11.3 Hz, 1H), 2.18-2.00 (m, 3H), 1.78 (d, J=9.9 Hz, 1H), 1.52 (d, J=6.9 Hz, 3H), 1.14 (s, 3H), 1.11 (d, J=6.7 Hz, 2H), 1.01 (s, 3H).
- For Example 49: LCMS (C24H31FN8O2) (ES, m/z): 483 [M+H]+. 1H NMR (400 MHz, Chloroform-d) δ 7.99 (d, J=10.8 Hz, 1H), 7.26 (s, 1H), 7.15 (d, J=7.6 Hz, 1H), 7.01 (s, 1H), 5.78 (s, 2H), 4.18 (s, 1H), 4.03 (m, 1H), 4.00 (s, 4H), 3.74 (m, 1H), 3.49 (s, 1H), 3.44 (dd, J=11.6, 3.9 Hz, 1H), 3.33 (dd, J=11.0, 4.2 Hz, 1H), 3.21 (t, J=11.3 Hz, 1H), 2.18-2.00 (m, 3H), 1.78 (d, J=9.7 Hz, 1H), 1.52 (d, J=6.9 Hz, 3H), 1.14 (s, 3H), 1.11 (m, J=6.9 Hz, 3H), 1.02 (s, 3H).
-
- To a reaction vial was added N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-((3S,6R, or 3R,6S)-6-methylpiperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine (Intermediate 96) (240 mg, 0.499 mmol, tBuXPhos-Pd G3 (119 mg, 0.150 mmol), rac-4-bromo-3-methyl-1-((1-((tetrahydro-2H-pyran-2-yl)oxy)cyclobutyl)methyl)-1H-pyrazole (Intermediate 31) (329 mg, 0.999 mmol), sodium tert-butoxide (288 mg, 3.00 mmol) and THF (5 mL). The mixture was sparged with nitrogen for 5 min. The mixture was stirred and heated at 100° C. for 19 h. The solvents were evaporated and the residue was purified by preparative silica gel TLC with 4% (7 M ammonia in MeOH) in DCM as eluent to afford a mixture of N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-((3S,6R or 3R,6S)-6-methyl-1-(3-methyl-1-((1-(((RS)-tetrahydro-2H-pyran-2-yl)oxy)cyclobutyl)methyl)-1H-pyrazol-4-yl)piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine and N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-((3S,6R or 3R,6S)-6-methyl-1-(5-methyl-1-((1-(((RS)-tetrahydro-2H-pyran-2-yl)oxy)cyclobutyl)methyl)-1H-pyrazol-4-yl)piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine.
-
- To the mixture of N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-((3S,6R or 3R,6S)-6-methyl-1-(3-methyl-1-((1-(((RS)-tetrahydro-2H-pyran-2-yl)oxy)cyclobutyl)methyl)-1H-pyrazol-4-yl)piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine and N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-((3S,6R or 3R,6S)-6-methyl-1-(5-methyl-1-((1-(((RS)-tetrahydro-2H-pyran-2-yl)oxy)cyclobutyl)methyl)-1H-pyrazol-4-yl)piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine (12.0 mg, 0.0186 mmol) was added TFA (2 mL). The mixture was stirred and heated at 60° C. for 1 h. The mixture was cooled to room temperature. The mixture was concentrated and the residue was purified by preparative silica gel TLC with 4% (7 M ammonia in MeOH) in DCM as eluent followed by reversed-phase HPLC (Waters SunFire C18 OBD Prep Column, 19 mm×100 mm MeCN/water w/0.1% TFA modifier as eluent) to afford 1-((4-((2R,5S or 2S,5R)-5-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-3-methyl-1H-pyrazol-1-yl)methyl)cyclobutan-1-ol (Example 50) and 1-((4-((2R,5S or 2S,5R)-5-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-5-methyl-1H-pyrazol-1-yl)methyl)cyclobutan-1-ol (Example 51).
- For Example 50: LCMS (C25H31FN8O2) (ES, m/z): 495 [M+H]+. 1H NMR (500 MHz, Methanol-d4) δ 8.02 (s, 1H), 7.95 (d, J=10.8 Hz, 1H), 7.26 (d, J=7.7 Hz, 1H), 4.22 (s, 2H), 4.18 (d, J=12.9 Hz, 1H), 4.03 (s, 3H), 3.91 (s, 2H), 3.74 (s, 1H), 3.57-3.43 (m, 1H), 2.46 (s, 3H), 2.36-2.26 (m, 1H), 2.22-2.12 (m, 3H), 2.04 (q, J=9.7 Hz, 3H), 1.84-1.73 (m, 1H), 1.68-1.58 (m, 1H), 1.27 (d, J=6.5 Hz, 3H).
- For Example 51: LCMS (C25H31FN8O2) (ES, m/z): 495 [M+H]+. 1H NMR (500 MHz, Methanol-d4) δ 7.98-7.91 (m, 1H), 7.82 (s, 1H), 7.26 (d, J=7.7 Hz, 1H), 4.27 (s, 2H), 4.03 (s, 3H), 3.96 (d, J=11.8 Hz, 2H), 3.76 (d, J=20.2 Hz, 1H), 2.61 (s, 2H), 2.45 (d, J=15.4 Hz, 2H), 2.40-2.29 (m, 2H), 2.26 (s, 1H), 2.15 (d, J=10.4 Hz, 3H), 2.11-1.97 (m, 3H), 1.89-1.74 (m, 1H), 1.75-1.58 (m, 1H), 1.28 (d, J=6.6 Hz, 3H).
- The example compounds of the invention in the following Table 17 were prepared in a manner similar to that described for Example 50 and Example 51 from the appropriate starting aryl halide and Intermediate 96.
-
TABLE 17 Observed Ex- Structure m/z ample Name [M + H]+ 52 483 1-(4-((2R,5S, or 2S,5R)-5-(5-amino-9-fluoro-8-methoxy- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin- 1-yl)-5-methyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol 53 483 1-(4-((2R,5S, or 2S,5R)-5-(5-amino-9-fluoro-8-methoxy- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin- 1-yl)-3-methyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol -
- To a reaction vial containing of solution of N-(2,4-dimethoxybenzyl)-9-fluoro-2-((3R,5S or 3S,5R)-5-fluoropiperidin-3-yl)-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-5-amine (Intermediate 99) (80.0 mg, 0.165 mmol) in THF (1.5 mL) was added 4-bromo-1-((1-((tetrahydro-2H-pyran-2-yl)oxy)cyclobutyl)methyl)-1H-pyrazole (Intermediate 23) (83.0 mg, 0.260 mmol) followed by tBuXPhos-Pd G3 (39.3 mg, 0.0500 mmol) and sodium tert-butoxide (47.6 mg, 0.495 mmol). The mixture was flushed with nitrogen for 10 min. The mixture was stirred and heated at 90° C. for 2 h. The solvents were evaporated. The resulting residue was purified by silica gel chromatography with 0-40% EtOAc:EtOH (3:1) in hexanes as eluent to afford N-(2,4-dimethoxybenzyl)-9-fluoro-2-((3R,5S or 3S,5R)-5-fluoro-1-(1-((1-((tetrahydro-2H-pyran-2-yl)oxy)cyclobutyl)methyl)-1H-pyrazol-4-yl)piperidin-3-yl)-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-5-amine. LCMS (C37H44F2N8O5) (ES, m/z): 719 [M+H]+.
-
- A mixture of N-(2,4-dimethoxybenzyl)-9-fluoro-2-((3R,5S or 3S,5R)-5-fluoro-1-(1-((1-((tetrahydro-2H-pyran-2-yl)oxy)cyclobutyl)methyl)-1H-pyrazol-4-yl)piperidin-3-yl)-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-5-amine (105 mg, 0.146 mmol) in TFA (1.2 mL) was stirred and heated at 60° C. for 1 h. The mixture was concentrated. The residue was purified by preparative silica gel TLC with 5% (7 M ammonia in MeOH) in DCM as eluent to afford 1-((4-((3R,5S or 3S,5R)-3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-fluoropiperidin-1-yl)-1H-pyrazol-1-yl)methyl)cyclobutan-1-ol. LCMS (C23H26F2N8O2) (ES, m/z): 485 [M+H]+.
- 1H NMR (400 MHz, Chloroform-d) δ 7.96 (d, J=10.7 Hz, 1H), 7.26 (s, 1H), 7.15 (t, J=3.8 Hz, 2H), 5.91 (s, 2H), 4.90 (dtt, J=48.1, 9.9, 4.7 Hz, 1H), 4.13 (s, 2H), 4.00 (s, 3H), 3.74-3.64 (m, 2H), 3.42 (d, J=12.6 Hz, 1H), 2.86 (t, J=11.4 Hz, 1H), 2.71 (dq, J=10.3, 7.2, 5.2 Hz, 2H), 2.17-1.92 (m, 3H), 1.88-1.73 (m, 2H), 1.57 (dq, J=18.2, 9.1 Hz, 2H).
- The example compounds of the invention in the following Table 18 were prepared in a manner similar to that described for the preparation of Example 54 from the appropriate starting aryl halide and Intermediate 99.
-
TABLE 18 Observed Structure m/z Example Name [M + H]+ 55 473 1-(4-((3R,5S or 3S,5R)-3-(5-amino-9-fluoro-8-methoxy- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-fluoropiperidin-1- yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol 56 485 9-fluoro-2-((3R,5S or 3S,5R)-5-fluoro-1-(1-(tetrahydro-2H- pyran-4-yl)-1H-pyrazol-4-yl)piperidin-3-yl)-8-methoxy- [1,2,4]triazolo[1,5-c]quinazolin-5-amine -
- To a reaction vial containing of solution of 2-((1R,5R or 1S,5S)-3-azabicyclo[3.1.0]hexan-1-yl)-N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-5-amine (Intermediate 97) (60.0 mg, 0.129 mmol) in THF (1.5 mL) was added 4-bromo-1-((1-((tetrahydro-2H-pyran-2-yl)oxy)cyclobutyl)methyl)-1H-pyrazole (Intermediate 23) (61.1 mg, 0.194 mmol) followed by tBuXPhos-Pd G3 (30.8 mg, 0.039 mmol) and sodium tert-butoxide (43.4 mg, 0.452 mmol). Nitrogen was bubbled through the mixture for 10 min. The mixture was stirred and heated at 90° C. for 18 h. The mixture was cooled to room temperature. The solvents were evaporated, and the resulting residue was purified by preparative silica gel TLC with 5% MeOH in DCM as eluent to afford N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-((1R,5R or 1S,5S)-3-(1-((1-((tetrahydro-2H-pyran-2-yl)oxy)cyclobutyl)methyl)-1H-pyrazol-4-yl)-3-azabicyclo[3.1.0]hexan-1-yl)[1,2,4]triazolo[1,5-c]quinazolin-5-amine. LCMS (C37H43FN8O5) (ES, m/z): 699 [M+H]+.
-
- A mixture of N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-((1R,5R or 1S,5S)-3-(1-((1-((tetrahydro-2H-pyran-2-yl)oxy)cyclobutyl)methyl)-1H-pyrazol-4-yl)-3-azabicyclo[3.1.0]hexan-1-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine (59 mg, 0.084 mmol) and TFA (1.0 mL) was stirred and heated at 60° C. for 1 h. The mixture was cooled to room temperature. The solvents were evaporated. The resulting residue was purified by preparative silica gel TLC with 8% (7 M ammonia in MeOH) in DCM as eluent. The obtained residue was further purified by preparative reversed-phase HPLC (Waters SunFire C18 OBD Prep Column, 19 mm×100 mm MeCN/H2O with 0.1% TFA modifier as eluent) to afford 1-((4-((1R,5R or 1S,5S)-1-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-1H-pyrazol-1-yl)methyl)cyclobutan-1-ol 2,2,2-trifluoroacetate). LCMS (C23H25FN8O2) (ES, m/z): 465 [M+H]+.
- 1H NMR (400 MHz, Chloroform-d) δ 7.96 (d, J=10.0 Hz, 1H), 7.27 (s, 1H), 7.21 (s, 1H), 7.06 (s, 1H), 4.18 (s, 2H), 4.08 (s, 3H), 3.79 (d, J=8.6 Hz, 1H), 3.69 (d, J=8.7 Hz, 1H), 3.54 (d, J=8.6 Hz, 2H), 3.35 (s, 2H), 3.20 (dd, J=8.8, 3.8 Hz, 2H), 2.32 (s, 1H), 2.13-2.04 (m, 3H), 1.75 (d, J=3.8 Hz, 2H), 1.58 (d, J=4.9 Hz, 1H).
- Example 58 in the following Table 19 was prepared in a manner similar to that described for the preparation of Example 57 from Intermediate 97 and the appropriate starting aryl halide.
-
- To a reaction vial was added N-(2,4-dimethoxybenzyl)-9-fluoro-2-((3S,5R or 3R,5S)-5-fluoropiperidin-3-yl)-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-5-amine (Intermediate 100) (50.0 mg, 0.103 mmol), tBuXPhos-Pd G3 (24.6 mg, 0.0310 mmol), 4-bromo-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole (Intermediate 15) (23.9 mg, 0.103 mmol), sodium tert-butoxide (59.5 mg, 0.619 mmol) and THF (1 mL). The mixture was flushed with nitrogen for 5 min. The mixture was stirred and heated at 100° C. for 4 h. The solvents were evaporated, and the resulting residue was purified by silica gel chromatography with 0-100% (30% MeOH in EtOAc) in hexanes, yielding N-(2,4-dimethoxybenzyl)-9-fluoro-2-((3S,5R or 3R,5S)-5-fluoro-1-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)piperidin-3-yl)-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-5-amine.
-
- To a reaction vial was added N-(2,4-dimethoxybenzyl)-9-fluoro-2-((3S,5R or 3R,5S)-5-fluoro-1-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)piperidin-3-yl)-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-5-amine (85.0 mg, 0.130 mmol) was added TFA (2 mL). The mixture was stirred and heated at 60° C. for 1 h. The solvents were evaporated, and the residue was purified by preparative reversed-phase HPLC (Waters SunFire C18 OBD Prep Column, 19 mm×100 mm MeCN/H2O with 0.1% TFA modifier as eluent), to afford 9-fluoro-2-((3S,5R or 3R,5S)-5-fluoro-1-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)piperidin-3-yl)-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-5-amine. LCMS (C23H26F2N8O2) (ES, m/z): 485 [M+H]+. 1H NMR (500 MHz, Methanol-d4) δ 7.93 (d, J=10.7 Hz, 1H), 7.51 (s, 1H), 7.38 (s, 1H), 7.23 (d, J=7.5 Hz, 1H), 4.95 (dt, J=10.3, 5.4 Hz, 1H), 4.32 (dq, J=11.0, 6.1, 5.6 Hz, 1H), 4.13-3.95 (m, 4H), 3.78 (d, J=11.1 Hz, 2H), 3.65-3.52 (m, 2H), 3.46 (t, J=11.2 Hz, 1H), 2.89 (t, J=11.4 Hz, 1H), 2.82-2.59 (m, 2H), 2.12-1.92 (m, 4H).
-
- A 5 mL microwave vial was charged with rac-2-(azepan-3-yl)-N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-5-amine (Intermediate 83) (100 mg, 0.208 mmol) and THF (1.3 mL). To the mixture was added 1-(4-bromo-1H-pyrazol-1-yl)-2-methylpropan-2-ol (Intermediate 4) (91.0 mg, 0.420 mmol), followed by tBuXPhos-Pd G3 (66.1 mg, 0.0830 mmol) and sodium tert-butoxide (80.0 mg, 0.832 mmol). Nitrogen was bubbled through the mixture for 10 min. The mixture was stirred and heated at 90° C. for 12 h. The mixture was cooled to room temperature, and then the solids were removed by filtration and washed with DCM. The solvents of the filtrate were evaporated. The resulting residue was dissolved in TFA (802 μL, 10.4 mmol) and heated at 50° C. for 3 h. The mixture was cooled to room temperature, and the solvents were evaporated. The resulting residue was purified by preparative reversed-phase HPLC (Waters SunFire C18 OBD Prep Column, 19 mm×100 mm MeCN/H2O with 0.1% TFA modifier as eluent) to yield the racemic product. The racemic mixture was resolved by chiral SFC separation (Chiral Technologies OJ-H 21×250 mm column with 25% (isopropanol w/0.1% NH4OH modifier) as co-solvent), to afford (R or S)-1-(4-(3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)azepan-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol (Example 60, first eluting peak) and (S or R)-1-(4-(3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)azepan-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol (Example 61, second eluting peak).
- For Example 60: LCMS (C23H29FN8O2) (ES, m/z): 469 [M+H]+. 1H NMR (499 MHz, DMSO-d6) δ 7.88 (d, J=11.0 Hz, 1H), 7.72 (d, J=26.0 Hz, 2H), 7.18 (d, J=7.9 Hz, 1H), 7.12 (s, 1H), 7.07 (s, 1H), 4.63 (s, 1H), 3.97 (s, 3H), 3.87 (s, 2H), 3.75 (dd, J=14.3, 3.9 Hz, 1H), 3.53 (dd, J=14.3, 10.0 Hz, 1H), 3.45 (dq, J=9.7, 5.0, 4.6 Hz, 1H), 3.37 (dd, J=14.0, 6.1 Hz, 1H), 3.23 (ddd, J=13.3, 7.6, 5.1 Hz, 1H), 2.07-1.82 (m, 3H), 1.71 (s, 1H), 1.58-1.45 (m, 2H), 1.03 (d, J=3.5 Hz, 6H).
- For Example 61: LCMS (C23H29FN8O2) (ES, m/z): 469 [M+H]+. 1H NMR (499 MHz, DMSO-d6) δ 7.88 (d, J=11.0 Hz, 1H), 7.70 (s, 2H), 7.18 (d, J=7.7 Hz, 1H), 7.13 (s, 1H), 7.07 (s, 1H), 4.62 (s, 1H), 3.97 (s, 3H), 3.87 (s, 2H), 3.75 (dd, J=14.4, 3.8 Hz, 1H), 3.53 (dd, J=14.2, 10.2 Hz, 1H), 3.45 (dt, J=9.5, 4.9 Hz, 1H), 3.38 (s, 1H), 3.24 (dd, J=13.6, 5.5 Hz, 2H), 2.08-1.84 (m, 3H), 1.71 (s, 1H), 1.50 (d, J=12.7 Hz, 2H), 1.03 (d, J=3.4 Hz, 6H).
- The example compounds of the invention in the following Table 20 were prepared in a manner similar to that described for the preparation of Example 60 and Example 61 from the appropriate starting amine and aryl halide, where the resulting isomeric mixture of the corresponding final compounds were separated by SFC.
-
TABLE 20 Observed Exam- Structure SFC m/z ple Name Conditions [M + H]+ 62 Peak 1; Chiral Technologies AD-H 21 × 250 mm column with 50% (IPA w/ 0.2% DIPA modifier) as co-solvent 459 (R or S)-1-(4-(3-(5-amino-9-fluoro-8-methoxy- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)-3- fluoropyrrolidin-1-yl)-1H-pyrazol-1-yl)-2- methylpropan-2-ol 63 Peak 2; Chiral Technologies AD-H 21 × 250 mm column with 50% (IPA w/ 0.2% DIPA modifier) as co-solvent 459 (S or R)-1-(4-(3-(5-amino-9-fluoro-8-methoxy- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)-3- fluoropyrrolidin-1-yl)-1H-pyrazol-1-yl)-2- methylpropan-2-ol 64 Peak 1; Chiral Technologies IC 21 × 250 mm column with 35% (MeOH w/ 0.1% NH4OH modifier) as co-solvent 470 (R or S)-3-(3-((R)-3-(5-amino-9-fluoro-8-methoxy- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidin-1-yl)- 1H-1,2,4-triazol-1-yl)-2-methylbutan-2-ol 65 Peak 2; Chiral Technologies IC 21 × 250 mm column with 35% (MeOH w/ 0.1% NH4OH modifier) as co-solvent 470 (S or R)-3-(3-((R)-3-(5-amino-9-fluoro-8-methoxy- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidin-1-yl)- 1H-1,2,4-triazol-1-yl)-2-methylbutan-2-ol 66 Peak 1; Chiralcel OJ- H 4.6 × 150 mm column with 40% (MeOH w/ 0.05% DEA modifier) as co-solvent 469 1-(4-((3S or 3R, 4S or 4R)-3-(5-amino-9-fluoro-8- methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-4- methylpiperidin-1-yl)-1H-pyrazol-1-yl)-2- methylpropan-2-ol 67 Peak 2; Chiralcel OJ- H 4.6 × 150 mm column with 40% (MeOH w/ 0.05% DEA modifier) as co-solvent 469 1-(4-((3R or 3S,4R or 4S)-3-(5-amino-9-fluoro-8- methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-4- methylpiperidin-1-yl)-1H-pyrazol-1-yl)-2- methylpropan-2-ol -
- To a 40 mL vial was added rac-N-(2,4-dimethoxybenzyl)-9-fluoro-2-((3R,5S or 3S,5R)-5-fluoropiperidin-3-yl)-7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-5-amine (Intermediate 102) (736 mg, 1.52 mmol), 1-(4-bromo-1H-pyrazol-1-yl)-2-methylpropan-2-ol (Intermediate 4) (998 mg, 4.56 mmol), tBuXPhos-Pd G3 (965 mg, 1.22 mmol), sodium tert-butoxide (876 mg, 9.11 mmol), and THF (15.0 mL). The mixture was purged with nitrogen for 5 min. The mixture was stirred and heated at 80° C. for 6 h. The mixture was cooled to room temperature. The solvents were evaporated, and the resulting residue was purified by silica gel chromatography with 0-100% EtOAc:EtOH (3:1) in hexanes as eluent to afford rac-1-(4-((3R,5S or 3S,5R)-3-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-fluoropiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol. LCMS (C31H36F2N8O4) (ES, m/z): 623 [M+H]+.
-
- To a 20 mL vial was added rac-1-(4-((3R,5S or 3S,5R)-3-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-fluoropiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol (550 mg, 0.883 mmol), and TFA (8.83 mL, 115 mmol). The mixture was stirred and heated at 50° C. for 2 h. The solvents were evaporated. To the resulting residue was added MeOH and the mixture was filtered. The solvents of the filtrate were evaporated. The racemic mixture was resolved by chiral SFC separation (Chiral Technologies AS-H 21×250 mm column with 15% (MeOH w/0.1% NH4OH modifier) as co-solvent) to afford 1-(4-((3R,5S or 3S,5R)-3-(5-amino-9-fluoro-7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-fluoropiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol (Example 68, first eluting peak) and 1-(4-((3S,5R or 3R,55)-3-(5-amino-9-fluoro-7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-fluoropiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol (Example 69, second eluting peak).
- For Example 68: LCMS (C22H26F2N8O2) (ES, m/z): 473 [M+H]+. 1H NMR (600 MHz, DMSO-d6) δ 7.82 (s, 2H), 7.43 (dd, J=8.3, 2.6 Hz, 1H), 7.37 (s, 1H), 7.28 (s, 1H), 7.18 (dd, J=11.0, 2.6 Hz, 1H), 4.94 (dtt, J=48.3, 10.3, 4.8 Hz, 1H), 4.65 (s, 1H), 3.93 (s, 3H), 3.89 (s, 2H), 3.78-3.71 (m, 1H), 3.66 (d, J=11.5 Hz, 1H), 3.40 (t, J=11.8 Hz, 1H), 2.75 (t, J=11.5 Hz, 1H), 2.66 (d, J=6.1 Hz, 1H), 2.58 (td, J=10.4, 5.2 Hz, 1H), 1.92 (p, J=11.3 Hz, 1H), 1.04 (s, 6H).
- For Example 69: LCMS (C22H26F2N8O2) (ES, m/z): 473 [M+H]+. 1H NMR (600 MHz, DMSO-d6) δ 7.82 (s, 1H), 7.44 (dd, J=8.3, 2.7 Hz, 1H), 7.37 (s, 1H), 7.28 (s, 1H), 7.19 (dd, J=11.1, 2.7 Hz, 1H), 4.95 (ddt, J=48.3, 10.4, 5.2 Hz, 1H), 4.64 (s, 1H), 3.94 (s, 2H), 3.89 (s, 1H), 3.74 (d, J=10.6 Hz, 1H), 3.66 (d, J=11.9 Hz, 1H), 3.40 (t, J=11.8 Hz, 1H), 2.74 (d, J=11.5 Hz, 1H), 2.65 (s, 1H), 2.58 (dt, J=10.3, 5.2 Hz, 1H), 1.97-1.89 (m, 1H), 1.04 (s, 6H).
- The example compounds of the invention in the following Table 21 were prepared in a manner similar to that described for the preparation of Example 68 and Example 69 from Intermediate 102 and the appropriate starting aryl halide, where the resulting isomeric mixture of the corresponding final compounds were separated by SFC.
-
TABLE 21 Observed Exam- Structure m/z ple Name SFC Conditions [M + H]+ 70 Peak 1; Phenomenex Lux-2 21 × 250 mm column with 40% (MeOH w/ 0.1% NH4OH modifier) as co-solvent 487 1-(4-((3R,5S or 3S,5R)-3-(5-amino-9-fluoro-7- methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5- fluoropiperidin-1-yl)-3-methyl-1H-pyrazol-1-yl)- 2-methylpropan-2-ol 71 Peak 2; Phenomenex Lux-2 21 × 250 mm column with 40% (MeOH w/ 0.1% NH4OH modifier) as co- solvent 487 1-(4-((3S,5R or 3R,5S)-3-(5-amino-9-fluoro-7- methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5- fluoropiperidin-1-yl)-3-methyl-1H-pyrazol-1-yl)- 2-methylpropan-2-ol 72 Peak 1; ES Industries CCA 21 × 250 mm column with 20% (MeOH w/ 0.1% NH4OH modifier) as co- solvent 485 1-((4-((3R,5S or 3S,5R)-3-(5-amino-9-fluoro-7- methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5- fluoropiperidin-1-yl)-1H-pyrazol-1- yl)methyl)cyclobutan-1-ol 73 Peak 2; ES Industries CCA 21 × 250 mm column with 20% (MeOH w/ 0.1% NH4OH modifier) as co- solvent 485 1-((4-((3S,5R or 3R,5S)-3-(5-amino-9-fluoro-7- methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5- fluoropiperidin-1-yl)-1H-pyrazol-1- yl)methyl)cyclobutan-1-ol -
- To a 20 mL vial was added rac-N-(2,4-dimethoxybenzyl)-9-fluoro-2-((3R,5R or 3S,5S)-5-fluoropiperidin-3-yl)-7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-5-amine (Intermediate 102) (434 mg, 0.896 mmol), 1-(4-bromo-1H-pyrazol-1-yl)-2-methylpropan-2-ol (Intermediate 4) (589 mg, 2.69 mmol), tBuXPhos-Pd G3 (569 mg, 0.717 mmol), sodium tert-butoxide (517 mg, 5.37 mmol) and THF (9.0 mL). The mixture was purged with nitrogen for 5 min. The mixture was stirred and heated at 80° C. for 6 h. The mixture was cooled to room temperature. The solvents were evaporated. The resulting residue was purified by silica gel chromatography with 30-50% EtOAc:EtOH (3:1) in hexane as eluent, yielding rac-1-(4-((3R,5R or 3S,5S)-3-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-fluoropiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol. LCMS (C31H36F2N8O4) (ES, m/z): 623 [M+H]+.
-
- To a 20 mL vial containing rac-1-(4-((3R,5R or 3S,5S)-3-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-fluoropiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol (439 mg, 0.705 mmol) was added TFA (7.05 mL, 92.0 mmol). The mixture was stirred and heated at 50° C. for 2 h. The solvents were evaporated. To the residue was added MeOH. The mixture was filtered, and then the solvents of the filtrate were evaporated. The racemic mixture was resolved by chiral SFC separation (Chiral Technologies AS-H 21×250 mm column with 15% (MeOH w/0.1% NH4OH modifier) as co-solvent), yielding 1-(4-((3R,5R or 3S,5S)-3-(5-amino-9-fluoro-7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-fluoropiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol (Example 74, first eluting peak) and 1-(4-((3R,5R or 35,55)-3-(5-amino-9-fluoro-7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-fluoropiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol (Example 75, second eluting peak).
- For Example 74: LCMS (C22H26F2N8O2) (ES, m/z): 473 [M+H]+. 1H NMR (499 MHz, DMSO-d6) δ 7.83 (s, 2H), 7.43 (dd, J=8.4, 2.7 Hz, 1H), 7.32 (s, 1H), 7.24 (s, 1H), 7.19 (d, J=10.0 Hz, 1H), 5.11 (d, J=46.5 Hz, 1H), 4.64 (s, 1H), 3.94 (s, 3H), 3.89 (s, 2H), 3.69-3.48 (m, 3H), 2.97-2.89 (m, 1H), 2.90-2.79 (m, 1H), 2.40 (s, 1H), 2.14 (dt, J=40.9, 11.8 Hz, 1H), 1.04 (s, 6H).
- For Example 75: LCMS (C22H26F2N8O2) (ES, m/z): 473 [M+H]+. 1H NMR (499 MHz, DMSO-d6) δ 7.83 (s, 2H), 7.43 (dd, J=8.4, 2.7 Hz, 1H), 7.32 (s, 1H), 7.24 (s, 1H), 7.19 (d, J=8.9 Hz, 1H), 5.11 (d, J=47.5 Hz, 1H), 3.94 (s, 3H), 3.89 (s, 2H), 3.67-3.50 (m, 3H), 2.97-2.90 (m, 1H), 2.90-2.79 (m, 1H), 2.41 (s, 1H), 2.14 (dt, J=40.8, 12.8 Hz, 1H), 1.04 (s, 6H).
- The example compounds of the invention in the following Table 22 were prepared in a manner similar to that described for the preparation of Example 74 and Example 75 from Intermediate 103 and the appropriate starting aryl halide, where the resulting isomeric mixture of the corresponding final compounds were separated by SFC.
-
TABLE 22 Observed Exam- Structure SFC m/z ple Name Conditions [M + H]+ 76 Peak 1; Phenomenex Lux-3 21 × 250 mm column with 15% (MeOH w/ 0.1% NH4OH modifier) as co-solvent 487 1-(4-((3R,5R or 3S,5S)-3-(5-amino-9-fluoro-7- methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5- fluoropiperidin-1-yl)-3-methyl-1H-pyrazol-1-yl)-2- methylpropan-2-ol 77 Peak 2; Phenomenex Lux-2 21 × 250 mm column with 15% (MeOH w/ 0.1% NH4OH modifier) as co-solvent 487 1-(4-((3S,5S or 3R,5R)-3-(5-amino-9-fluoro-7- methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5- fluoropiperidin-1-yl)-3-methyl-1H-pyrazol-1-yl)-2- methylpropan-2-ol 78 Peak 1; Chiral Technologies OJ-H 21 × 250 mm column with 20% (MeOH w/ 0.1% NH4OH modifier) as co-solvent 485 1-((4-((3R,5R or 3S,5S)-3-(5-amino-9-fluoro-7- methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5- fluoropiperidin-1-yl)-1H-pyrazol-1- yl)methyl)cyclobutan-1-ol 79 Peak 2; Chiral Technologies OJ-H 21 × 250 mm column with 20% (MeOH w/ 0.1% NH4OH modifier) as co-solvent 485 1-((4-((3S,5S or 3R,5R)-3-(5-amino-9-fluoro-7- methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5- fluoropiperidin-1-yl)-1H-pyrazol-1- yl)methyl)cyclobutan-1-ol -
- Step 1 of Example 80 and Example 81 was conducted in a manner similar to step 1 of Example 74 and Example 75, with Intermediate 101 and Intermediate 4 to afford rac-1-(4-((3R,5R or 3S,5S)-3-(5 #2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-fluoropiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol. LCMS (C31H36F2N8O4) (ES, m/z): 623 [M+H]+.
-
- Step 2 of Example 80 and Example 81 was conducted in a manner similar to step 2 of Example 74 and Example 75, where rac-1-(4-((3R,5R or 3S,5S)-3-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-fluoropiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol is converted to the racemic mixture of the corresponding final compounds. The racemic mixture was resolved by chiral SFC separation (Chiral Technologies OJ-H 21×250 mm column with 25% (MeOH w/0.2% DIPA modifier) as co-solvent), to afford 1-(4-((3R,5R or 3S,5S)-3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-fluoropiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol (Example 80, first eluting peak) and 1-(4-((3S,5S or 3R,5R)-3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-fluoropiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol (Example 81, second eluting peak).
- For Example 80: LCMS (C22H26F2N8O2) (ES, m/z): 473 [M+H]+. 1H NMR (500 MHz, Methanol-d4) δ 7.94 (d, J=10.8 Hz, 1H), 7.48 (s, 1H), 7.42 (s, 1H), 7.24 (d, J=7.5 Hz, 1H), 5.12 (d, J=46.8 Hz, 1H), 4.02 (d, J=3.8 Hz, 3H), 3.84 (d, J=12.4 Hz, 1H), 3.82-3.74 (m, 1H), 3.74-3.62 (m, 1H), 3.11 (t, J=11.0 Hz, 1H), 3.08-2.95 (m, 1H), 2.67 (s, 1H), 2.59 (s, 1H), 2.31-2.12 (m, 1H), 1.16 (s, 6H).
- For Example 81: LCMS (C22H26F2N8O2) (ES, m/z): 473 [M+H]+. 1H NMR (500 MHz, Methanol-d4) δ 7.94 (d, J=10.8 Hz, 1H), 7.50 (s, 1H), 7.43 (s, 1H), 7.24 (d, J=7.5 Hz, 1H), 5.13 (d, J=47.0 Hz, 1H), 4.02 (d, J=4.8 Hz, 3H), 3.85 (d, J=11.0 Hz, 1H), 3.82-3.73 (m, 1H), 3.73-3.60 (m, 1H), 3.11 (t, J=11.0 Hz, 1H), 3.04 (dd, J=36.0, 12.9 Hz, 1H), 2.59 (s, 1H), 2.30-2.12 (m, 1H), 1.16 (s, 6H).
-
- To a reaction vial containing a solution of (R)—N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-(piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine (Intermediate 82) (150 mg, 0.322 mmol) in THF (3.0 mL) was added 2-(4-bromo-1H-pyrazol-1-yl)-1-methylcyclopentanol 2,2,2-trifluoroacetate (Intermediate 6) (184 mg, 0.514 mmol) followed by tBuXPhos-Pd G3 (77.0 mg, 0.0960 mmol) and sodium tert-butoxide (93.0 mg, 0.965 mmol). Nitrogen was bubbled through the mixture for 10 min. The mixture was stirred and heated at 90° C. for 4 h. The mixture was cooled to room temperature, and then the resulting residue was purified by silica gel chromatography with 0-40% EtOAc:EtOH (3:1) in hexane as eluent, yielding a diastereomeric mixture of products. The mixture was purified by SFC separation (Chiral Technologies OJ-H 21×250 mm column with 30% MeOH as co-solvent), yielding peak 1 and peak 2 corresponding to (1R or 1S,2R or 2S)-2-(4-((R)-3-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidin-1-yl)-1H-pyrazol-1-yl)-1-methylcyclopentan-1-ol and (1S or 1R,2S or 2R)-2-(4-((R)-3-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidin-1-yl)-1H-pyrazol-1-yl)-1-methylcyclopentan-1-ol. For peak 1, LCMS (C33H39FN8O4) (ES, m/z): 631 [M+H]+. For peak 2, LCMS (C33H39FN8O4) (ES, m/z): 631 [M+H]+.
-
- Step 2 of Example 82 and Example 83 was conducted in a manner similar to step 2 of Example 40, where peak 1 and peak 2 obtained from step 1 were converted to (1R or 1S,2R or 2S)-2-(4-((R)-3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidin-1-yl)-1H-pyrazol-1-yl)-1-methylcyclopentan-1-ol and (1S or 1R,2S or 2R)-2-(4-((R)-3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidin-1-yl)-1H-pyrazol-1-yl)-1-methylcyclopentan-1-ol, which are the final compounds of Example 82 and Example 83, respectively.
- For Example 82: LCMS (C24H29FN8O2) (ES, m/z): 481 [M+H]+. 1H NMR (400 MHz, Chloroform-d) δ 7.97 (d, J=10.7 Hz, 1H), 7.31 (s, 1H), 7.13 (d, J=7.6 Hz, 1H), 7.07 (s, 1H), 5.89 (s, 2H), 4.36 (t, J=8.8 Hz, 1H), 3.99 (s, 3H), 3.68 (dd, J=11.5, 3.6 Hz, 1H), 3.38 (tt, J=7.5, 3.8 Hz, 2H), 2.95 (t, J=11.1 Hz, 1H), 2.67 (td, J=11.3, 4.4 Hz, 1H), 2.40-2.07 (m, 3H), 1.99-1.73 (m, 7H), 0.88 (s, 3H).
- For Example 83: LCMS (C24H29FN8O2) (ES, m/z): 481 [M+H]+. 1H NMR (400 MHz, Chloroform-d) δ 7.97 (d, J=10.7 Hz, 1H), 7.31 (s, 1H), 7.13 (d, J=7.6 Hz, 1H), 7.07 (s, 1H), 5.88 (s, 2H), 4.35 (t, J=8.7 Hz, 1H), 3.99 (s, 3H), 3.74-3.64 (m, 1H), 3.43-3.31 (m, 2H), 2.95 (t, J=11.1 Hz, 1H), 2.67 (td, J=11.2, 4.5 Hz, 1H), 2.39-2.10 (m, 3H), 2.00-1.74 (m, 7H), 0.88 (s, 3H).
- The example compounds of the invention in the following Table 23 were prepared in a manner similar to that described for the preparation of Example 82 and Example 83 from the appropriate intermediates and starting materials. In each case, an SFC separation was conducted on the intermediate mixture formed from the first step. The SFC conditions to isolate these intermediates are shown with the corresponding final products formed from the second step.
-
TABLE 23 SFC Conditions Observed Exam- Structure for intermediate m/z ple Name from step 1 [M + H]+ 84 Peak 1; Whelko- 1 21 × 250 mm column with 50% (MeOH w/ 0.2% DIPA modifier) as co-solvent 467 (1R or 1S,2R or 2S)-2-(4-((R)-3-(5-amino-9- fluoro-8-methoxy-[1,2,4[triazolo[1,5- c]quinazolin-2-yl)piperidin-1-yl)-1H-pyrazol- 1-yl)cyclopentan-1-ol 85 Peak 2; Whelko- 1 21 × 250 mm column with 50% (MeOH w/ 0.2% DIPA modifier) as co-solvent 467 (1S or 1R,2S or 2R)-2-(4-((R)-3-(5-amino-9- fluoro-8-methoxy-[1,2,4[triazolo]1,5- c]quinazolin-2-yl)piperidin-1-yl)-1H-pyrazol- 1-yl)cyclopentan-1-ol 86 Peak 1; Chiral Technologies AD-H 21 × 250 mm column with 45% (IPA 1:1 w/ 0.2% DIPA modifier) as co-solvent 483 (S or R)-3-(4-((R)-3-(5-amino-9-fluoro-7- methoxy-[1,2,4[triazolo[1,5-c]quinazolin-2- yl)piperidin-1-yl)-3-methyl-1H-pyrazol- 1-yl)-2-methylbutan-2-ol 87 Peak 2; Chiral Technologies AD-H 21 × 250 mm column with 45% (IPA 1:1 w/ 0.2% DIPA modifier) as co-solvent 483 (R or S)-3-(4-((R)-3-(5-amino-9-fluoro-7- methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2- yl)piperidin-1-yl)-3-methyl-1H-pyrazol-1-yl)- 2-methylbutan-2-ol -
- The mixture of N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-((3R,6S or 3S,6R)-6-methyl-1-(14(1R or 1S,2R or 2S)-2-((tetrahydro-2H-pyran-2-yl)oxy)cyclopentyl)-1H-pyrazol-4-yl)piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine (Intermediate 120) (5.0 mg, 7.0 μmol) in TFA (0.3 mL) was heated at 60° C. for 25 min. The mixture was concentrated. The residue was purified by preparative silica gel TLC eluting with 5% (7 M ammonia in MeOH) in DCM to afford (1R or 1S,2R or 2S)-2-(4-((2S,5R or 2R,5S)-5-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-1H-pyrazol-1-yl)cyclopentan-1-ol. LCMS (C24H29FN8O2) (ES, m/z): 481 [M+H]+. 1H NMR (400 MHz, Chloroform-d) δ 7.99 (d, J=10.7 Hz, 1H), 7.25 (s, 1H), 7.15 (d, J=7.6 Hz, 1H), 7.02 (s, 1H), 5.87 (s, 2H), 4.35 (d, J=7.5 Hz, 1H), 4.21 (d, J=8.7 Hz, 1H), 4.01 (s, 3H), 3.74 (d, J=6.5 Hz, 1H), 3.47-3.41 (m, 1H), 3.32 (d, J=11.0 Hz, 1H), 3.23 (d, J=11.3 Hz, 1H), 2.26 (m, 1H), 2.16-2.08 (m, 3H), 2.08-2.00 (m, 2H), 1.90-1.71 (m, 4H), 1.13 (d, J=6.7 Hz, 3H).
-
- Example 89 was prepared from Intermediate 121 in a manner similar to Example 88 to afford (1S or 1R,2S or 2R)-2-(4-((2S,5R or 2R,5S)-5-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-1H-pyrazol-1-yl)cyclopentan-1-ol. LCMS (C24H29FN8O2) (ES, m/z): 481 [M+H]+. 1H NMR (400 MHz, Chloroform-d) δ 7.99 (d, J=10.7 Hz, 1H), 7.25 (s, 1H), 7.15 (d, J=7.6 Hz, 1H), 7.01 (s, 1H), 5.81 (s, 2H), 4.36 (q, J=7.1 Hz, 1H), 4.27-4.15 (m, 1H), 4.00 (s, 3H), 3.79-3.67 (m, 1H), 3.44 (dd, J=11.5, 4.2 Hz, 1H), 3.37-3.28 (m, 1H), 3.22 (t, J=11.1 Hz, 1H), 2.34-2.21 (m, 1H), 2.19-1.96 (m, 4H), 1.94-1.62 (m, 6H), 1.12 (d, J=6.7 Hz, 3H).
-
- To a solution of rac-1-(4-((3S,5R or 3R,5S)-3-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-methylpiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol (Intermediate 122) (150 mg, 0.242 mmol) in DCM (2 mL) was added TFA (2 mL). The mixture was stirred at 50° C. for 10 h. The mixture was concentrated. The racemic mixture was purified and resolved by chiral SFC (Phenomenex Lux-2 4.6×150 mm column with 0-40% (EtOH w/0.05% DEA) as cosolvent), to yield 1-(4-((3R,5S or 3S,5R)-3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-methylpiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol (first eluting peak) and 1-(4-((3S,5R or 3R,5S)-3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-methylpiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol (second eluting peak), corresponding to Example 90 and Example 91, respectively For Example 90: LCMS (C23H29FN8O2) (ES, m/z) [M+H]+: 469. 1H NMR (400 MHz, METHANOL-d4) δ=7.66 (d, J=10.8 Hz, 1H), 7.32 (d, J=10.0 Hz, 2H), 6.94 (d, J=7.8 Hz, 1H), 3.98 (s, 2H), 3.91 (s, 3H), 3.81-3.71 (m, 1H), 3.38 (br d, J=9.0 Hz, 1H), 3.32-3.22 (m, 2H), 2.69 (t, J=11.6 Hz, 1H), 2.32-2.13 (m, 2H), 2.02-1.89 (m, 1H), 1.36 (q, J=12.5 Hz, 1H), 1.14 (s, 6H), 1.00 (d, J=6.6 Hz, 3H).
- For Example 91: LCMS (C23H29FN8O2) (ES, m/z) [M+H]+: 469. 1H NMR (400 MHz, METHANOL-d4) δ=7.68 (d, J=10.8 Hz, 1H), 7.37 (d, J=19.1 Hz, 2H), 6.98 (d, J=7.8 Hz, 1H), 3.99 (s, 2H), 3.93 (s, 3H), 3.84-3.76 (m, 1H), 3.42 (br d, J=10.3 Hz, 1H), 3.34-3.26 (m, 2H), 2.77 (t, J=11.6 Hz, 1H), 2.32-2.20 (m, 2H), 1.99 (br d, J=6.6 Hz, 1H), 1.40 (q, J=12.5 Hz, 1H), 1.19-1.09 (m, 7H), 1.02 (d, J=6.6 Hz, 3H).
-
- To a solution of 1-(4-((3R,5R and 3S,5S)-3-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-methylpiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol (Intermediate 123) (20 mg, 0.032 mmol) in DCM (2 mL) was added TFA (2 mL). The mixture was stirred and heated at 45° C. for 5 h. The mixture was concentrated. The residue was purified by reversed-phase HPLC (Waters SunFire C18 OBD Prep Column, 19 mm×100 mm with MeCN/water (w/0.1% TFA as modifier) as eluent), to yield 1-(4-((3R,5R and 3S,5S)-3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-methylpiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol. LCMS (C23H29FN8O2) (ES, m/z) [M+H]+: 469. 1H NMR (400 MHz, METHANOL-d4) δ=8.02-7.90 (m, 2H), 7.73 (s, 1H), 7.27-7.15 (m, 1H), 4.22 (br d, J=11.2 Hz, 1H), 4.13-4.07 (m, 2H), 4.00 (s, 4H), 3.78-3.65 (m, 2H), 3.57-3.47 (m, 1H), 3.11 (t, J=11.0 Hz, 1H), 2.54 (br d, J=13.7 Hz, 1H), 2.27-2.14 (m, 1H), 1.90-1.80 (m, 1H), 1.17 (s, 6H), 1.11 (d, J=6.8 Hz, 3H).
-
- To a stirred mixture of TFA (0.5 mL) in DCM (0.5 mL) was added (R)-5-(4-(3-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidin-1-yl)-1H-pyrazol-1-yl)pentan-2-one (Intermediate 124) (28.0 mg, 0.0450 mmol). The mixture was stirred and heated at 50° C. for 15 h. The mixture was cooled, and the solvents were evaporated. The resulting residue was purified by preparative reversed-phase HPLC (Waters SunFire C18 OBD Prep Column, 19 mm×100 mm with MeCN/water (w/0.1% TFA as modifier) as eluent), to yield (R)-5-(4-(3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidin-1-yl)-1H-pyrazol-1-yl)pentan-2-one. LCMS (C23H27FN8O2) (ES, m/z) [M+H]+: 467.
- 1H NMR (400 MHz, CD3OD) δ: 7.90 (d, J=10.96 Hz, 1H), 7.36 (s, 1H), 7.31 (s, 1H), 7.19 (d, J=7.45 Hz, 1H), 4.62 (br s, 1H), 4.05 (t, J=6.80 Hz, 2H), 3.99 (s, 3H), 3.67-3.78 (m, 1H), 3.39 (br d, J=11.84 Hz, 1H), 2.95 (t, J=11.18 Hz, 1H), 2.60-2.74 (m, 1H), 2.44 (t, J=7.02 Hz, 2H), 2.28 (br d, J=9.21 Hz, 1H), 2.10 (s, 3H), 2.02 (quin, J=7.02 Hz, 2H), 1.81-1.95 (m, 3H).
-
- To a stirred mixture of (R)-5-(4-(3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidin-1-yl)-1H-pyrazol-1-yl)pentan-2-one (Example 93) (15.0 mg, 0.0320 mmol) in THF (2 mL) was added NaBH4 (2.4 mg, 0.064 mmol). The mixture was stirred at 25° C. for 3 h. The reaction mixture was quenched with 1 M aqueous HCl (2 mL). The mixture was extracted with EtOAc (2×30 mL), and the organic layer was dried over sodium sulfate, filtered and then the solvents of the filtrate were evaporated. The residue was purified by reversed-phase HPLC (Waters SunFire C18 OBD Prep Column, 19 mm×100 mm with MeCN/water (w/0.1% TFA as modifier) as eluent), to afford (S or R)-5-(4-((R)-3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidin-1-yl)-1H-pyrazol-1-yl)pentan-2-ol and (R or S)-5-(4-((R)-3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidin-1-yl)-1H-pyrazol-1-yl)pentan-2-ol, corresponding to Example 94 and Example 95, respectively.
- For Example 94: LCMS (C23H29FN8O2) (ES, m/z) [M+H]+: 469. 1H NMR (400 MHz, CD3OD) δ: 7.94 (d, J=10.83 Hz, 1H), 7.89 (s, 1H), 7.67 (s, 1H), 7.25 (d, J=7.63 Hz, 1H), 4.19 (br t, J=7.10 Hz, 2H), 4.08-4.00 (m, 4H), 3.78-3.66 (m, 2H), 3.57 (br s, 2H), 3.36 (t, J=1.68 Hz, 1H), 2.40 (br s, 1H), 2.16-1.85 (m, 5H), 1.48-1.36 (m, 2H), 1.17 (d, J=6.26 Hz, 3H).
- For Example 95: LCMS (C23H29FN8O2) (ES, m/z) [M+H]+: 469. 1H NMR (400 MHz, CD3OD) δ: 7.95 (d, J=10.68 Hz, 1H), 7.46 (s, 1H), 7.37 (s, 1H), 7.24 (d, J=7.78 Hz, 1H), 4.11 (t, J=6.87 Hz, 3H), 4.03 (s, 4H), 3.84-3.62 (m, 3H), 3.48-3.37 (m, 5H), 3.31 (br s, 1H), 3.19 (s, 1H), 2.33 (s, 1H), 2.02-1.77 (m, 5H), 1.41 (br d, J=5.80 Hz, 2H), 1.16 (d, J=6.10 Hz, 3H).
-
- To a stirred mixture of 1,4-dioxaspiro[4.5]decan-8-ol (5.00 g, 31.6 mmol), PPh3 (12.4 g, 47.4 mmol), and 4-nitro-1H-pyrazole (4.29 g, 37.9 mmol) in DCM (80 mL) was added di-tert-butyl diazene-1,2-dicarboxylate (18.2 g, 79.0 mmol) under a nitrogen atmosphere, and the mixture was stirred at 25° C. for 10 h. The mixture was concentrated and purified by silica gel chromatography with 10-25% EtOAc in petroleum ether as eluent to afford 4-nitro-1-(1,4-dioxaspiro[4.5]decan-8-yl)-1H-pyrazole. LCMS (C11H15N3O4) (ES, m/z) [M+H]+: 254.
-
- To a stirred mixture of 4-nitro-1-(1,4-dioxaspiro[4.5]decan-8-yl)-1H-pyrazole (5.50 g, 21.7 mmol) in MeOH (50 mL) and EtOAc (50 mL) was added 10% Pd/C (0.462 g, 4.34 mmol). The mixture was purged with nitrogen twice and was stirred under an atmosphere of hydrogen for 6 h. The mixture was filtered and the solvents were evaporated. The resulting residue was purified by silica gel chromatography with 20-50% EtOAc in petroleum ether as eluent to afford 1-(1,4-dioxaspiro[4.5]decan-8-yl)-1H-pyrazol-4-amine. LCMS (C11H17N3O2) (ES, m/z) [M+H]+: 224.
-
- To a stirred mixture of 1-(1,4-dioxaspiro[4.5]decan-8-yl)-1H-pyrazol-4-amine (2.14 g, 9.60 mmol) and lithium tetrafluoroborate (0.600 g, 6.40 mmol) in TFE (15 mL) was added ethyl 2-methylene-5-oxohexanoate (1.00 g, 5.88 mmol). The mixture was stirred and heated at 80° C. for 10 h. The mixture was cooled, diluted with water (15 mL), and extracted with EtOAc (2×30 mL). The organic layer was dried (anhydrous Na2SO4), filtered, and the solvents of the filtrate were evaporated. To the resulting residue was added MeOH (15 mL) and 10% Pd/C (0.068 g, 0.64 mmol). The mixture was degassed and purged with nitrogen twice and was stirred under an atmosphere of hydrogen for 10 h. The mixture was filtered, and then the filtrate was concentrated. The residue was purified by silica gel chromatography with 10-50% EtOAc in petroleum ether as eluent to afford ethyl 1-(1-(1,4-dioxaspiro[4.5]decan-8-yl)-1H-pyrazol-4-yl)-6-methylpiperidine-3-carboxylate. LCMS (C20H31N3O4) (ES, m/z) [M+H]+: 378.
-
- To a stirred mixture of 1-(1-(1,4-dioxaspiro[4.5]decan-8-yl)-1H-pyrazol-4-yl)-6-methylpiperidine-3-carboxylate (450 mg, 1.192 mmol) in EtOH (10 mL) was added hydrazine hydrate (382 mg, 11.92 mmol). The mixture was stirred and heated at 80° C. for 10 h. The mixture was concentrated to afford 1-(1-(1,4-dioxaspiro[4.5]decan-8-yl)-1H-pyrazol-4-yl)-6-methylpiperidine-3-carbohydrazide, which was used without further purification. LCMS (C18H29N5O3) (ES, m/z) [M+H]+ 364.
-
- A 40 mL vial was charged with 1-(1-(1,4-dioxaspiro[4.5]decan-8-yl)-1H-pyrazol-4-yl)-6-methylpiperidine-3-carbohydrazide (351 mg, 0.967 mmol) and DCM (2 mL). To this mixture was added AcOH (0.025 mL, 0.44 mmol) followed by 2-((((2,4-dimethoxybenzyl)imino)methylene)amino)-5-fluoro-4-methoxybenzonitrile (Intermediate 37) (300 mg, 0.879 mmol). The mixture was stirred and heated at 35° C. for 16 h. The mixture was then concentrated. The resulting residue was purified by silica gel chromatography with 10-50% EtOAc in petroleum ether as eluent to afford the cis diastereomer, 2-((3R,6S and 3S,6R)-1-(1-(1,4-dioxaspiro[4.5]decan-8-yl)-1H-pyrazol-4-yl)-6-methylpiperidin-3-yl)-N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-5-amine. LCMS (C36H43FN8O5) (ES, m/z) [M+H]+ 687.
-
- To a stirred mixture of 2-((3R,6S and 3S,6R)-1-(1-(1,4-dioxaspiro[4.5]decan-8-yl)-1H-pyrazol-4-yl)-6-methylpiperidin-3-yl)-N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-5-amine (40.0 mg, 0.0580 mmol) in DCM (2 mL) was added TFA (2 mL). The mixture was stirred for 10 h. The mixture was concentrated. To the residue was added saturated aqueous sodium bicarbonate. The mixture was extracted with EtOAc (2×5 mL). The combined organic layer was dried over anhydrous Na2SO4, filtered, and the solvents of the filtrate were evaporated. The resulting residue was purified by preparative silica gel TLC with EtOAc as eluent to afford rac-4-(4-((2S,5R or 2R,5S)-5-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-1H-pyrazol-1-yl)cyclohexanone. LCMS (C25H29FN8O2) (ES, m/z) [M+H]+ 493.
-
- To a stirred mixture of rac-4-(4-((2S,5R or 2R,5S)-5-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-1H-pyrazol-1-yl)cyclohexanone (18 mg, 0.037 mmol) in THF (5 mL) was added methylmagnesium bromide (0.122 mL, 0.365 mmol). The mixture was stirred at 0° C. for 12 h. The reaction mixture was quenched with aqueous NH4Cl (5 mL) and extracted with EtOAc (2×5 mL). The combined organic layer was dried over anhydrous Na2SO4, filtered, and the solvents of the filtrate were evaporated. The resulting residue was purified by preparative reversed-phase HPLC (Waters SunFire C18 OBD Prep Column, 19 mm×100 mm with MeCN/water (w/0.1% TFA modifier) as eluent) to afford (1r,4s or 1r,4r)-4-(4-((2S,5R and 2R,5S)-5-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-1H-pyrazol-1-yl)-1-methylcyclohexan-1-ol and (1r,4r or 1r,4s)-4-(4-((2S,5R and 2R,5S)-5-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-1H-pyrazol-1-yl)-1-methylcyclohexan-1-ol, corresponding to Example 96 and Example 97.
- For Example 96: 1H NMR (400 MHz, MeOD) δ 7.98 (s, 1H), 7.92 (d, J=11.2 Hz, 1H), 7.68 (s, 1H), 7.22 (d, J=7.6 Hz, 1H), 4.18-4.29 (m, 1H), 4.01 (s, 4H), 3.85-3.97 (m, 2H), 3.63-3.65 (m, 1H), 2.46-2.48 (m, 1H), 2.15-2.30 (m, 2H), 1.90-2.13 (m, 5H), 1.73-1.84 (m, 2H), 1.60-1.72 (m, 2H), 1.31 (s, 3H), 1.20 (d, J=6.8 Hz, 3H). LCMS (C26H33FN8O2) (ES, m/z) [M+H]+ 509.
- For Example 97: 1H NMR (400 MHz, MeOD) δ 8.01 (s, 1H), 7.91 (d, J=11.2 Hz, 1H), 7.70 (s, 1H), 7.21 (d, J=8.0 Hz, 1H), 4.06-4.25 (m, 2H), 4.00 (s, 3H), 3.84-3.98 (m, 2H), 3.65-3.68 (m, 1H), 2.48-2.50 (m, 1H), 2.10-2.32 (m, 3H), 2.02-2.08 (m, 2H), 1.87-1.96 (m, 2H), 1.80-1.82 (m, 2H), 1.56-1.67 (m, 2H), 1.25 (s, 3H), 1.21 (d, J=6.8 Hz, 3H). LCMS (C26H33FN8O2) (ES, m/z) [M+H]+ 509.
-
- A mixture of methylmagnesium bromide (0.318 ml, 0.955 mmol, 3 M in diethyl ether) in THF (1.00 ml) was cooled at 0° C. To the mixture was added 2-(4-((R)-3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidin-1-yl)-1H-pyrazol-1-yl)cyclobutanone (Intermediate 125) (86.0 mg, 0.191 mmol) in THF (1.0 mL) The mixture was stirred at 0° C. for 5 h. To the mixture was added water (3 mL), and then the mixture was extracted with EtOAc (3×20 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and the solvents of the filtrate were evaporated. The resulting residue was purified by preparative silica gel TLC with 10% MeOH in DCM as eluent. The isomeric mixture was purified by SFC (OJ-3 100×4.6 mm column with 5-40% (MeOH w/0.05% DEA) as co-solvent) to afford (1S or 1R,2S or 2R)-2-(4-((R)-3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidin-1-yl)-1H-pyrazol-1-yl)-1-methylcyclobutan-1-ol (first eluting peak) and (1R or 1S,2R or 2S)-2-(4-((R)-3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidin-1-yl)-1H-pyrazol-1-yl)-1-methylcyclobutan-1-ol (second eluting peak) corresponding to Example 98 and Example 99, respectively.
- For Example 98: LCMS (C23H27FN8O2) (ES, m/z) [M+H]+: 467. 1H NMR (400 MHz, CD3OD) δ=7.98 (d, J=10.68 Hz, 1H), 7.37 (s, 1H), 7.15 (d, J=7.48 Hz, 1H), 7.09 (s, 1H), 5.78 (br s, 2H), 4.48-4.34 (m, 1H), 4.05-3.96 (m, 3H), 3.81-3.73 (m, 1H), 3.72-3.62 (m, 1H), 3.42-3.31 (m, 2H), 2.98 (t, J=11.06 Hz, 1H), 2.76-2.59 (m, 1H), 2.52-2.38 (m, 1H), 2.33-2.15 (m, 3H), 2.06-1.77 (m, 5H), 1.42 (s, 3H).
- For Example 99: LCMS (C23H27FN8O2) (ES, m/z) [M+H]+: 467. 1H NMR (400 MHz, CD3OD) δ=7.98 (d, J=10.68 Hz, 1H), 7.37 (s, 1H), 7.15 (d, J=7.48 Hz, 1H), 7.09 (s, 1H), 5.78 (br s, 2H), 4.48-4.34 (m, 1H), 4.05-3.96 (m, 3H), 3.81-3.73 (m, 1H), 3.72-3.62 (m, 1H), 3.42-3.31 (m, 2H), 2.98 (t, J=11.06 Hz, 1H), 2.76-2.59 (m, 1H), 2.52-2.38 (m, 1H), 2.33-2.15 (m, 3H), 2.06-1.77 (m, 5H), 1.42 (s, 3H).
-
- BSA (2 mL, 8.18 mmol) was added to N′-(2-amino-6-fluoro-8-methoxyquinazolin-4-yl)-1-(1-methyl-1H-pyrazol-4-yl)piperidine-3-carbohydrazide (Intermediate 104) (25.0 mg, 0.0600 mmol), and the mixture was stirred at 120° C. for 2 h. The solvents were then evaporated. The resulting residue was diluted with chloroform/isopropanol—3:1 (5 mL), washed with aqueous sodium bicarbonate (saturated, 5 mL), and the organic layer collected using a phase separator column (25 mL) and concentrated. The residue was purified by preparative reversed-phase HPLC (Waters SunFire C18 OBD Prep Column, 19 mm×100 mm MeCN/water (with 0.1% TFA modifier) as eluent). The racemic mixture was resolved by chiral SFC separation (OJ-H column 21×250 mm column with 20% (MeOH w/0.25% DMEA modifier) as co-solvent) to afford (R or S)-9-fluoro-7-methoxy-2-(1-(1-methyl-1H-pyrazol-4-yl)piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine (Example 100, first eluting peak). LCMS (C19H21FN8O) (ES, m/z): 397 [M+H]+. 1H NMR (600 MHz, DMSO-d6) δ 7.79 (s, 2H), 7.42 (dd, J=8.4, 2.7 Hz, 1H), 7.30 (s, 1H), 7.21-7.16 (m, 2H), 3.93 (s, 3H), 3.72 (s, 3H), 3.60 (dd, J=11.5, 3.7 Hz, 1H), 3.32-3.30 (m, 1H), 3.29-3.23 (m, 1H), 2.83 (t, J=11.1 Hz, 1H), 2.58-2.52 (m, 2H), 2.20-2.12 (m, 1H), 1.88-1.81 (m, 1H), 1.80-1.74 (m, 2H).
- The example compounds of the invention in following Table 24 were prepared from the appropriate intermediates in a manner similar to Example 100, with the exception that the starting materials were enantiopure, thus no SFC separation was conducted for these examples.
-
TABLE 24 Ob- served Ex- m/z am- Structure [M + ple Name H]+ 101 385 (R or S)-8,9-difluoro-2-(1-(1-methyl-1H-pyrazol-4- yl)piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine 102 367 (R or S)-9-fluoro-2-(1-(1-methyl-1H-pyrazol-4-yl)piper- idin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine 103 385 (R or S)-7,9-difluoro-2-(1-(1-methyl-1H-pyrazol-4- yl)piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine 104 413 (R or S)-9-chloro-7-methoxy-2-(1-(1-methyl-1H-pyrazol-4- yl)piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine 105 397 (R or S)-9-chloro-7-methyl-2-(1-(1-methyl-1H-pyrazol-4- yl)piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine 106 383 (R or S)-9-chloro-2-(1-(1-methyl-1H-pyrazol-4-yl)piper- idin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine 107 385 (R or S)-9,10-difluoro-2-(1-(1-methyl-1H-pyrazol-4- yl)piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine 108 379 (R or S)-9-methoxy-2-(1-(1-methyl-1H-pyrazol-4- yl)piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin- 5-amine -
- To a 100 mL round bottom flask was added (3R,6S)-1-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-6-methylpiperidine-3-carbohydrazide (Intermediate 61) (1.00 g, 3.39 mmol), 2-((((2,4-dimethoxybenzyl)imino)-methylene)amino)-5-fluoro-4-methoxybenzonitrile (Intermediate 37) (1.21 g, 3.55 mmol) and DCM (10 mL). The mixture was stirred at room temperature for 18 h. The mixture was concentrated, and the resulting residue was purified by silica gel chromatography with 0-100% EtOAc in hexane as eluent, yielding 1-(4-((2S,5R)-5-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol. LCMS (C32H39FN8O4) (ES, m/z): 619 [M+H]+. The absolute configuration of the product of Step 1 was assigned to be (2S,5R) using Vibrational Circular Dichroism (VCD) spectroscopy with confidence. Analysis was done comparing experimental data to the calculated VCD and IR spectra of the product possessing the (2S,5R) configuration. The experimental VCD spectrum of the product matched well with the calculated (2S,5R) spectrum over the region from 1000-1500 cm-1, resulting in an assignment of (2S,5R).
-
- To a 20 mL vial was added 1-(4-((2S,5R)-5-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol (962 mg, 1.56 mmol) and TFA (7 mL). The mixture was stirred and heated at 50° C. for 1 h. The mixture was then concentrated. To the resulting residue was added 1 M aqueous HCl (50 mL) and DCM (50 mL). The aqueous layer was washed with DCM (2×50 mL), then filtered. The pH of the aqueous layer was then adjusted to ˜pH 10 with 10 M aqueous NaOH. The aqueous layer was extracted with 10% MeOH in DCM (2×100 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and the solvents of the filtrate were evaporated. The resulting residue was purified by silica gel chromatography with 0-10% MeOH in DCM, yielding 1-(4-((2S,5R)-5-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol (Example 109). LCMS (C23H29FN8O2) (ES, m/z): 469 [M+H]+. 1H NMR (499 MHz, DMSO-d6) δ 7.90 (d, J=11.0 Hz, 1H), 7.72 (s, 2H), 7.20 (s, 1H), 7.19 (d, J=7.9 Hz, 1H), 7.15 (s, 1H), 3.69 (d, J=6.7 Hz, 1H), 3.35 (d, J=3.9 Hz, 1H), 3.20 (dt, J=11.1, 5.8 Hz, 1H), 3.10 (t, J=11.5 Hz, 1H), 2.00 (d, J=6.1 Hz, 3H), 1.70 (d, J=9.3 Hz, 1H), 1.03 (d, J=4.4 Hz, 9H).
- The example compounds of the invention in the following Table 25 were prepared in a manner similar to that described for the preparation of Example 109 from the appropriate hydrazide and carbodiimide intermediates.
-
TABLE 25 Observed Exam- Structure m/z ple Name [M + H]+ 110 473 1-(4-((2S,5R)-5-(5-amino-8-chloro-9-fluoro- [1,2,4]triazolo[1,5-c[quinazolin-2-yl)-2-methylpiperidin-1- yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol 111 457 1-(4-((2S,5R)-5-(5-amino-7,9-difluoro-[1,2,4[triazolo[1,5- c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-1H-pyrazol-1- yl)-2-methylpropan-2-ol 112 453 1-(4-((2S,5R)-5-(5-amino-9-fluoro-8-methyl- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1- yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol 113 417 (R)-7,9-dichloro-2-(1-(1-methyl-1H-pyrazol-4-yl)piperidin- 3-yl)-[1,2,4[triazolo[1,5-c]quinazolin-5-amine -
- To a 2 dram vial was added 1-(1-(2-hydroxy-2-methylpropyl)-3-methyl-1H-pyrazol-4-yl)-6-methylpiperidine-3-carbohydrazide (Intermediate 63) (133 mg, 0.431 mmol) and 2-((((2,4-dimethoxybenzyl)imino)methylene)amino)-5-fluoro-3-methoxybenzonitrile (Intermediate 38) (140 mg, 0.410 mmol). To the mixture was added dioxane (1.6 mL) and acetic acid (24 μL, 0.41 mmol), and then the mixture was stirred and then heated at 60° C. for 2 h. The mixture was then allowed to slowly cool to room temperature. The mixture was diluted with DCM (10 mL) and washed with saturated aqueous sodium bicarbonate (2×10 mL) and brine. The combined organic layers were dried over anhydrous MgSO4, filtered, and the solvents of the filtrate were evaporated. The residue was purified by silica gel chromatography with 10-100% EtOAc in hexanes to afford 1-(4-(5-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-3-methyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol as a mixture of racemic diastereomers. LCMS (C33H42FN8O4) (ES, m/z): 633 [M+H]+
-
- To a 20 mL vial was added 1-(4-(5-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-3-methyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol (80 mg, 0.126 mmol) followed by TFA (0.13 mL). The mixture was stirred and heated at 50° C. for 2 h. The mixture was then concentrated. The resulting residue was purified by preparative reversed-phase HPLC (Waters SunFire C18 OBD Prep Column, 19 mm×100 mm with MeCN/water w/0.1% TFA as eluent) to afford the product as a mixture of diastereomers. The four isomers were resolved by chiral SFC separation (IC, 21×250 mm column with 35% (2-Propanol w/0.1% NH4OH modifier) as cosolvent) to afford 1-(4-((2R or 2S,5R or 5S)-5-(5-amino-9-fluoro-7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-3-methyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol (Example 114, first eluting peak) and 1-(4-((2S or 2R,5R or 5S)-5-(5-amino-9-fluoro-7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-3-methyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol (Example 115, second eluting peak) and 1-(4-((2S or 2R,5S or 5R)-5-(5-amino-9-fluoro-7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-3-methyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol (Example 116, third eluting peak) and 1-(4-((2R or 2S,5S or 5R)-5-(5-amino-9-fluoro-7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-3-methyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol (Example 117, fourth eluting peak).
- For Example 114: LCMS (C24H32FN8O2) (ES, m/z): 483 [M+H]+. 1H NMR (499 MHz, DMSO-d6) δ 7.70 (br s, 2H), 7.42 (dd, J=8.4, 2.7 Hz, 1H), 7.30 (s, 1H), 7.18 (dd, J=11.1, 2.7 Hz, 1H), 4.75 (br s, 1H), 3.93 (s, 3H), 3.80 (s, 2H), 3.37-3.31 (m, 1H), 3.23-3.16 (m, 1H), 2.18-2.15 (m, 1H), 2.01 (s, 3H), 2.09-1.94 (m, 2H), 1.70-1.59 (m, 1H), 1.25-1.10 (m, 2H), 1.04 (s, 3H), 1.03 (s, 3H), 0.95 (d, J=12.0 Hz, 3H).
- For Example 115: LCMS (C24H32FN8O2) (ES, m/z): 483 [M+H]+. 1H NMR (499 MHz, DMSO-d6) δ 7.61 (br s, 2H), 7.40 (dd, J=8.2, 2.4 Hz, 1H), 7.30 (s, 1H), 7.18 (dd, J=11.0, 2.1 Hz, 1H), 4.75 (br s, 1H), 3.93 (s, 3H), 3.80 (s, 2H), 3.38-3.30 (m, 1H), 3.19-3.12 (m, 1H), 2.15-2.10 (m, 1H), 2.07 (s, 3H), 2.09-1.94 (m, 2H), 1.72-1.65 (m, 1H), 1.25-1.10 (m, 2H), 1.07 (s, 3H), 1.06 (s, 3H), 0.93 (d, J=11.8 Hz, 3H).
- For Example 116: LCMS (C24H32FN8O2) (ES, m/z): 483 [M+H]+. 1H NMR (499 MHz, DMSO-d6) δ 7.52 (br s, 2H), 7.41 (dd, J=8.4, 2.7 Hz, 1H), 7.39 (s, 1H), 7.15-7.11 (m, 1H), 4.41 (br s, 1H), 3.90 (s, 3H), 3.85 (s, 2H), 3.30-3.20 (m, 1H), 3.13-3.09 (m, 1H), 2.18-2.11 (m, 1H), 2.00 (s, 3H), 2.00-1.84 (m, 2H), 1.75-1.66 (m, 1H), 1.24-1.10 (m, 2H), 1.04 (m, 6H), 0.91 (d, J=6.5 Hz, 3H).
- For Example 117: LCMS (C24H32FN8O2) (ES, m/z): 483 [M+H]+. 1H NMR (499 MHz, DMSO-d6) δ 7.77 (br s, 2H), 7.43 (dd, J=8.4, 2.7 Hz, 1H), 7.33 (s, 1H), 7.18 (dd, J=11.1, 2.7 Hz, 1H), 4.60 (br s, 1H), 3.94 (s, 3H), 3.83 (s, 2H), 3.26-3.22 (m, 1H), 3.10-3.06 (m, 1H), 2.18-2.16 (m, 1H), 2.04 (s, 3H), 2.01-1.87 (m, 2H), 1.75-1.69 (m, 1H), 1.24-1.10 (m, 2H), 1.03 (s, 3H), 1.02 (s, 3H), 0.93 (d, J=6.5 Hz, 3H).
- The example compounds of the invention in the following Table 26 were prepared in a manner similar to that described for the preparation of Examples 114-117 from the appropriate hydrazide and carbodiimide intermediates. The resulting isomeric mixtures were resolved by SFC separation.
-
TABLE 26 Observed Exam- Structure SFC m/z ple Name Conditions [M + H]+ 118 Peak 1; Lux-4 21 × 250 mm column with 35% (MeOH w/0.1% NH4OH modifier) as co-solvent 469 1-(4-((2R or 2S,5R or 5S)-5-(5-amino-9-fluoro-7- methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2- methylpiperidin-1-yl)-1H-pyrazol-1-yl)-2- methylpropan-2-ol 119 Peak 2; Lux-4 21 × 250 mm column with 35% (MeOH w/0.1% NH4OH modifier) as co-solvent 469 1-(4-((2S or 2R,5S or 5R)-5-(5-amino-9-fluoro-7- methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2- methylpiperidin-1-yl)-1H-pyrazol-1-yl)-2- methylpropan-2-ol 120 Peak 3; Lux-4 21 × 250 mm column with 35% (MeOH w/0.1% NH4OH modifier) as co-solvent 469 1-(4-((2R or 2S,5S or 5R)-5-(5-amino-9-fluoro-7- methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2- methylpiperidin-1-yl)-1H-pyrazol-1-yl)-2- methylpropan-2-ol 121 Peak 4; Lux-4 21 × 250 mm column with 35% (MeOH w/0.1% NH4OH modifier) as co-solvent 469 1-(4-((2S or 2R,5R or 5S)-5-(5-amino-9-fluoro-7- methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2- methylpiperidin-1-yl)-1H-pyrazol-1-yl)-2- methylpropan-2-ol 122 Peak 1; IC-3 4.6 × 100 mm column with 40% (IPA w/ 0.05% DEA modifier) as cosolvent 469 2-(4-((2R or 2S,5R or 5S)-5-(5-amino-9-fluoro-7- methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2- methylpiperidin-1-yl)-1H-pyrazol-1-yl)-2- methylpropan-1-ol 123 Peak 2; IC-3 4.6 × 100 mm column with 40% (IPA w/ 0.05% DEA modifier) as cosolvent 469 2-(4-((2S or 2R,5S or 5R)-5-(5-amino-9-fluoro-7- methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2- methylpiperidin-1-yl)-1H-pyrazol-1-yl)-2- methylpropan-1-ol 124 Peak 3; IC-3 4.6 × 100 mm column with 40% (IPA w/ 0.05% DEA modifier) as cosolvent 469 2-(4-((2R or 2S,5S or 5R)-5-(5-amino-9-fluoro-7- methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2- methylpiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-1-ol 125 Peak 4; IC-3 4.6 × 100 mm column with 40% (IPA w/ 0.05% DEA modifier) as cosolvent 469 2-(4-((2S or 2R,5R or 5S)-5-(5-amino-9-fluoro-7- methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2- methylpiperidin-1-yl)-1H-pyrazol-1-yl)-2- methylpropan-1-ol 126 Peak 1 and 2 overlapping; Chiralcel OJ- 3 4.6 × 100 mm column with 5-40% (MeOH w/ 0.05% DEA modifier) as cosolvent 469 rac-2-(4-((2R or 2S,5R or 5S)-5-(5-amino-9-fluoro- 8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2- methylpiperidin-1-yl)-1H-pyrazol-1-yl)-2- methylpropan-1-ol 127 Peak 3; Chiralcel OJ- 3 4.6 × 100 mm column with 5-40% (MeOH w/ 0.05% DEA modifier) as cosolvent 469 2-(4-((2R or 2S,5S or 5R)-5-(5-amino-9-fluoro-8- methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2- methylpiperidin-1-yl)-1H-pyrazol-1-yl)-2- methylpropan-1-ol 128 Peak 4; Chiralcel OJ- 3 4.6 × 100 mm column with 5-40% (MeOH w/ 0.05% DEA modifier) as cosolvent 469 1-(4-((2S or 2R,5R or 5S)-3-(5-amino-9-fluoro-8- methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-4- methylpiperidin-1-yl)-1H-pyrazol-1-yl)-2- methylpropan-2-ol -
- A 1-dram vial was charged with the mixture of (R)—N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-(1-(3-methyl-1H-pyrazol-4-yl)piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine and (R)—N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-(1-(5-methyl-1H-pyrazol-4-yl)piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine (Intermediate 117) (391 mg, 0.715 mmol) and (chloromethyl)(methyl)sulfane (359 μL, 4.29 mmol) in dioxane (7.0 mL). To the mixture was added cesium carbonate (466 mg, 1.43 mmol), and then the mixture was stirred and heated at 75° C. for 60 h. The mixture was cooled to room temperature. The mixture was diluted with water and DCM. The mixture was poured into a phase separator. The DCM layer was collected and concentrated. The resulting residue was purified by silica gel column chromatography with 0-10% MeOH in DCM as eluent to afford the mixture of (R)—N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-(1-(3-methyl-1-((methylthio)methyl)-1H-pyrazol-4-yl)piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine and (R)—N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-(1-(5-methyl-1-((methylthio)methyl)-1H-pyrazol-4-yl)piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine. LCMS (C30H35FN8O3S) (ES, m/z): 607 [M+H]+.
-
- The mixture of (R)—N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-(1-(3-methyl-1-((methylthio)methyl)-1H-pyrazol-4-yl)piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine and (R)—N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-(1-(5-methyl-1-((methylthio)methyl)-1H-pyrazol-4-yl)piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine (328 mg, 0.541 mmol) was dissolved in acetone (4 mL) and water (1.35 mL). To the mixture was added Oxone® (potassium peroxymonosulfate, 665 mg, 1.08 mmol). The mixture was stirred for 10 min at room temperature. The mixture was concentrated to remove the acetone, diluted with water and DCM, and the organic layer was collected via a phase separator. The organic layer was concentrated. To the resulting residue was added and TFA (2.08 mL, 27.0 mmol), and the mixture was stirred and heated at 50° C. for 16 h. The mixture was then diluted with water and DCM, and the DCM layer was collected via a phase separator and concentrated. The resulting residue was purified by preparative reversed-phase HPLC (Waters SunFire C18 OBD Prep Column, 19 mm×100 mm, MeCN/water (w/0.1% TFA modifier) as eluent) to afford (R)-9-fluoro-8-methoxy-2-(1-(3-methyl-1-((methylsulfonyl)methyl)-1H-pyrazol-4-yl)piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine, TFA (Example 129, first eluting peak) and (R)-9-fluoro-8-methoxy-2-(1-(5-methyl-1-((methylsulfonyl)methyl)-1H-pyrazol-4-yl)piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine, TFA, (Example 130, second eluting peak).
- For Example 129: LCMS (C21H25FN8O3S) (ES, m/z): 489 [M+H]+. 1H NMR (500 MHz, DMSO-d6) δ 7.87 (d, J=10.9 Hz, 1H), 7.77 (s, 1H), 7.61 (s, 1H), 7.19 (d, J=7.9 Hz, 1H), 5.67 (s, 2H), 3.97 (s, 3H), 3.44 (m, 1H), 3.17 (s, 1H), 2.99 (s, 3H), 2.31 (s, 3H), 2.20 (m, 1H), 1.87 (m, 3H).
- For Example 130: LCMS (C21H25FN8O3S) (ES, m/z): 489 [M+H]+. 1H NMR (500 MHz, DMSO-d6) δ 7.87 (dd, J=10.9, 3.6 Hz, 1H), 7.78 (s, 2H), 7.58 (s, 1H), 7.19 (d, J=7.8 Hz, 1H), 5.52 (s, 2H), 3.97 (s, 3H), 3.48 (d, J=9.4 Hz, 1H), 3.32 (d, J=10.1 Hz, 1H), 3.21 (d, J=11.2 Hz, 1H), 2.98 (s, 3H), 2.65 (m, 1H), 2.18 (s, 3H), 1.97-1.71 (m, 3H).
- The example compounds of the invention in the following Table 27 were prepared in a manner similar to that described for the preparation of Example 129 and Example 130 from the appropriate intermediates and commercially available starting materials.
-
TABLE 27 Observed Exam- Structure m/z [M + ple Name H]+ 131 475 (R)-9-fluoro-8-methoxy-2-(1-(1-((methylsulfonyl)methyl)-1H- pyrazo1-4-yl)piperidin-3-yl)-[1,2,4]triazolo[1,5-c] quinazolin-5-amine 132 525 (R)-2-(1-(3-(difluoromethyl)-1-((methylsulfonyl)methyl)-1H- pyrazol-4-yl)piperidin-3-yl)-9-fluoro-8-methoxy- [1,2,4]triazolo[1,5-c]quinazolin-5-amine -
- To a reaction vial was added (S or R)—N-(2,4-dimethoxybenzyl)-9-fluoro-2-(3-fluoropiperidin-3-yl)-7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-5-amine (Intermediate 90) (78 mg, 0.161 mmol), 1-(4-bromo-1H-pyrazol-1-yl)-2-methylpropan-2-ol (Intermediate 4) (52.9 mg, 0.241 mmol), tBuXPhos-Pd G3 (38.4 mg, 0.048 mmol), and sodium tert-butoxide (93 mg, 0.97 mmol) in THF (3 mL). The mixture was flushed with nitrogen for 10 min. The mixture was stirred and heated at 90° C. for 16 h. The mixture was cooled to room temperature, filtered, and the solvents of the filtrate were evaporated. The residue was purified by silica gel chromatography with 0-8% MeOH in DCM (with 0.2% NH4OH) as eluent to afford (S or R)-1-(4-(3-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-3-fluoropiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol. LCMS (C31H36F2N8O4) (ES, m/z): 623 [M+H]+.
-
- An 8 mL scintillation vial was charged with (S or R)-1-(4-(3-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-3-fluoropiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol (70.0 mg, 0.112 mmol) and TFA (750 μL, 9.73 mmol). The mixture was stirred and heated at 40° C. for 2 h. The mixture was then cooled, and the solvents were evaporated. The resulting residue was purified by preparative reversed-phase HPLC (Waters SunFire C18 OBD Prep Column, 19 mm×100 mm MeCN/H2O with 0.05% TFA as eluent) to afford (S or R)-1-(4-(3-(5-amino-9-fluoro-7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-3-fluoropiperidin-1-yl)-1H-pyrazol-1-yl)-2 methylpropan-2-ol 2,2,2-trifluoroacetate. LCMS (C22H26F2N8O2) (ES, m/z): 473 [M+H]+. 1H NMR (500 MHz, DMSO-d6) δ 7.89 (s, 2H), 7.48 (dd, J=8.3, 2.7 Hz, 1H), 7.30 (s, 1H), 7.24 (d, J=0.7 Hz, 1H), 7.21 (dd, J=11.1, 2.8 Hz, 1H), 3.93 (s, 3H), 3.88 (s, 2H), 3.68-3.47 (m, −1H), 3.45-3.42 (m, 1H), 3.22-3.08 (m, 1H), 2.84-2.65 (m, 1H), 2.45-2.18 (m, 2H), 1.99 (d, J=9.7 Hz, 1H), 1.80 (dd, J=9.0, 4.0 Hz, 1H), 1.03 (d, J=2.7 Hz, 6H).
- Example 134 in the following Table 28 was prepared from Intermediate 91 and the appropriate starting materials in a manner similar to that described for the preparation of Example 133.
-
- A mixture of 1-(4-((2R or 2S,5S or 5R)-5-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-ethylpiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol (Intermediate 113) (28.0 mg, 0.0440 mmol) in TFA (50.5 mg, 0.443 mmol) was heated at 60° C. for 1 h. The solvents were evaporated, and the resulting residue was purified by preparative reversed-phase HPLC (Waters SunFire C18 OBD Prep Column, 19 mm×100 mm MeCN/H2O with 0.1% TFA as eluent) to afford 1-(4-((2R or 2S,5S or 5R)-5-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-ethylpiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol.: LCMS (C24H31FN8O2) (ES, m/z): 483 [M+H]+. 1H NMR (500 MHz, Methanol-d4) δ 7.97-7.89 (m, 2H), 7.70 (s, 1H), 7.24 (d, J=7.5 Hz, 1H), 4.12 (s, 2H), 4.08-3.92 (m, 5H), 3.72-3.57 (m, 2H), 2.52-2.38 (m, 1H), 2.31-2.14 (m, 2H), 2.09-1.98 (m, 1H), 1.75-1.56 (m, 2H), 1.18 (s, 6H), 0.94 (t, J=7.4 Hz, 3H).
-
- Example 136 was prepared from Intermediate 114 in a manner similar to that described for the preparation of Example 135. LCMS (C24H31FN8O2) (ES, m/z): 483 [M+H]+. 1H NMR (500 MHz, Methanol-d4) δ 7.93 (d, J=11.9 Hz, 2H), 7.70 (s, 1H), 7.24 (d, J=7.5 Hz, 1H), 4.12 (s, 2H), 4.07-3.93 (m, 5H), 3.69-3.58 (m, 2H), 2.51-2.37 (m, 1H), 2.32-2.15 (m, 2H), 2.10-1.99 (m, 1H), 1.74-1.58 (m, 2H), 1.17 (s, 6H), 0.94 (t, J=7.3 Hz, 3H).
-
- Example 137 was prepared from Intermediate 115 in a manner similar to that described for the preparation of Example 135. LCMS (C24H31FN8O2) (ES, m/z): 483 [M+H]+. 1H NMR (500 MHz, Methanol-d4) δ 8.11 (s, 1H), 7.90-7.81 (m, 2H), 7.21 (d, J=7.5 Hz, 1H), 4.14 (d, J=20.7 Hz, 3H), 3.98 (d, J=12.7 Hz, 4H), 3.72-3.54 (m, 2H), 2.56 (d, J=16.8 Hz, 1H), 2.45 (d, J=20.5 Hz, 1H), 2.21-2.07 (m, 1H), 1.98-1.82 (m, 1H), 1.81-1.69 (m, 1H), 1.56-1.43 (m, 1H), 1.19 (s, 6H), 0.97 (t, J=7.3 Hz, 3H).
-
- Example 138 was prepared from Intermediate 116 in a manner similar to that described for the preparation of Example 135. LCMS (C24H31FN8O2) (ES, m/z): 483 [M+H]+. 1H NMR (500 MHz, Methanol-d4) δ 8.13 (s, 1H), 7.86 (d, J=13.4 Hz, 2H), 7.21 (d, J=7.6 Hz, 1H), 4.15 (d, J=13.4 Hz, 3H), 3.99 (d, J=8.8 Hz, 4H), 3.74-3.54 (m, 2H), 2.57 (d, J=11.0 Hz, 1H), 2.50-2.39 (m, 1H), 2.24-2.05 (m, 1H), 1.96-1.83 (m, 1H), 1.82-1.67 (m, 1H), 1.59-1.42 (m, 1H), 1.18 (s, 6H), 0.97 (t, J=7.5 Hz, 3H).
-
- To a 20 mL vial was added rac-3-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidin-2-one (Intermediate 89) (0.102 g, 0.212 mmol), 1-(4-iodo-1H-pyrazol-1-yl)-2-methylpropan-2-ol (0.172 g, 0.646 mmol), copper(I) iodide (42.7 mg, 0.224 mmol), potassium phosphate (267 mg, 1.26 mmol), and anhydrous DMF (2.1 mL).
- The mixture was sparged with nitrogen for 5 min. To the mixture was added N1,N2-dimethylethane-1,2-diamine (0.046 mL, 0.43 mmol). The mixture was stirred and heated at 100° C. for 2 h. The mixture was purified by reversed-phase HPLC (Waters SunFire C18 OBD Prep Column, 19 mm×100 mm with MeCN/H2O (with 0.1% TFA) as eluent), to afford rac-3-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-1-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)piperidin-2-one. LCMS (C31H35FN8O5) (ES, m/z): 619 [M+H]+.
-
- To a 20 mL vial was added rac-3-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-1-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)piperidin-2-one (11.9 mg, 0.0192 mmol) and TFA (0.26 mL). The mixture was stirred and heated at 50° C. for 1 h. The mixture was concentrated. The residue was purified by preparative reversed-phase HPLC (Waters SunFire C18 OBD Prep Column, 19 mm×100 mm with
- MeCN/H2O (with 0.1% TFA) as eluent) to afford rac-3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-1-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)piperidin-2-one. LCMS (C22H25FN8O3) (ES, m/z): 469 [M+H]+. 1H NMR (499 MHz, DMSO-d6) δ 8.05 (s, 1H), 7.88 (d, J=11.0 Hz, 1H), 7.79 (br s, 2H), 7.66 (s, 1H), 7.18 (d, J=7.8 Hz, 1H), 4.18 (t, J=7.8 Hz, 1H), 3.99-3.93 (m, 5H), 3.86-3.76 (m, 2H), 2.28-2.16 (m, 3H), 2.10-2.00 (m, 1H), 1.03 (s, 3H), 1.03 (s, 3H).
-
- To a 20 mL vial was added (R)—N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-(morpholin-2-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine (Intermediate 87) (49.4 mg, 0.105 mmol), a mixture of 1-(4-bromo-3-methyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol and 1-(4-bromo-5-methyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol (Intermediate 7) (31.0 mg, 0.133 mmol), tBuXPhos-Pd G3 (33.5 mg, 0.0422 mmol), sodium tert-butoxide (60.8 mg, 0.633 mmol), and anhydrous THF (1.5 mL). The mixture was sparged with nitrogen. The mixture was then stirred and heated at 100° C. for several minutes, then cooled to 23° C., and additional THF (1 mL) was added. The mixture was stirred and heated at 80° C. for 14 h. Additional amounts of the mixture of 1-(4-bromo-3-methyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol and 1-(4-bromo-5-methyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol (Intermediate 7) (42.5 mg, 0.182 mmol) and tBuXPhos-Pd G3 (33.5 mg, 0.0422 mmol) were added. The mixture was stirred and heated at 80° C. for 8 h. The mixture was diluted with DCM and MeOH and filtered through Celite® (diatomaceous earth). The filtrate was concentrated. The resulting residue was purified by silica gel chromatography with 0-100% EtOAc:EtOH (3:1) in hexanes as eluent to afford a mixture of (R)-1-(4-(2-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)morpholino)-3-methyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol and (R)-1-(4-(2-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)morpholino)-5-methyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol. LCMS (C31H37FN8O5) (ES, m/z): 621 [M+H]+.
-
- To a 4 mL vial was added the mixture of (R)-1-(4-(2-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)morpholino)-3-methyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol and (R)-1-(4-(2-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)morpholino)-5-methyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol (4.6 mg, 0.0074 mmol) and TFA (0.10 mL). The mixture was stirred at 23° C. for 2 h. The mixture was then stirred and heated at 50° C. for 50 min. To a separate vial was added the mixture of (R)-1-(4-(2-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)morpholino)-3-methyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol and (R)-1-(4-(2-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)morpholino)-5-methyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol (35.6 mg, 0.0574 mmol) and TFA (0.78 mL), and this mixture was stirred and heated at 50° C. for 50 min. The contents of the two reaction vials were combined and concentrated to a residue. The residue was suspended in MeOH and filtered. The filtrate was concentrated to a residue. The resulting residue was subjected to chiral SFC separation (Chiral Technologies OJ-H 21×250 mm column with 15% (MeOH w/0.1% NH4OH modifier) as co-solvent), to afford (R)-1-(4-(2-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)morpholino)-3-methyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol (Example 140) as peak 1, and a second peak. The second peak contained an impurity, and therefore was purified by SFC (Chiral Technologies AS-H 21×250 mm column with 20% (MeOH w/0.1% NH4OH modifier) as co-solvent), yielding (R)-1-(4-(2-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)morpholino)-5-methyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol (Example 141).
- For Example 140: LCMS (C22H27FN8O3) (ES, m/z): 471 [M+H]+. 1H NMR (499 MHz, DMSO-d6) δ 7.90 (d, J=10.9 Hz, 1H), 7.80 (br s, 2H), 7.37 (s, 1H), 7.18 (d, J=7.9 Hz, 1H), 4.95 (dd, J=10.0, 2.5 Hz, 1H), 4.62 (s, 1H), 4.07-4.00 (m, 1H), 3.97 (s, 3H), 3.88 (td, J=11.1, 2.3 Hz, 1H), 3.83 (s, 2H), 3.07-2.97 (m, 2H), 2.72 (td, J=11.5, 3.1 Hz, 1H), 2.12 (s, 3H), 1.03 (s, 3H), 1.02 (s, 3H).
- For Example 141: LCMS (C22H27FN8O3) (ES, m/z): 471 [M+H]+. 1H NMR (499 MHz, DMSO-d6) δ 7.89 (d, J=10.9 Hz, 1H), 7.79 (br s, 2H), 7.34 (s, 1H), 7.18 (d, J=7.9 Hz, 1H), 4.95 (dd, J=9.7, 2.6 Hz, 1H), 4.63 (s, 1H), 4.08-4.00 (m, 1H), 3.96 (s, 3H), 3.92-3.82 (m, 3H), 3.25-3.20 (m, 1H), 3.11 (dd, J=11.5, 10.0 Hz, 1H), 2.96-2.90 (m, 1H), 2.87 (td, J=11.3, 3.1 Hz, 1H), 2.22 (s, 3H), 1.07 (s, 3H), 1.06 (s, 3H).
-
- To a 20 mL vial was added rac-2-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)thiomorpholine 1,1-dioxide (Intermediate 88) (100 mg, 0.194 mmol), tBuXPhos-Pd G3 (154 mg, 0.194 mmol), a mixture of 1-(4-bromo-3-methyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol and 1-(4-bromo-5-methyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol (Intermediate 7) (140 mg, 0.598 mmol), and dry THF (3 mL). The mixture was sparged with nitrogen for 4 min. To the mixture was added sodium tert-butoxide (112 mg, 1.16 mmol). The mixture was stirred and heated at 80° C. for 18 h. The mixture was concentrated. The resulting residue was suspended in DCM, mixed with Celite® (diatomaceous earth), and filtered. The filtrate was concentrated. The resulting residue was purified by silica gel chromatography with 0-70% EtOAc:EtOH (3:1) in hexanes as eluent, yielding a mixture of rac-2-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-4-(1-(2-hydroxy-2-methylpropyl)-3-methyl-1H-pyrazol-4-yl)thiomorpholine 1,1-dioxide and rac-2-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-4-(1-(2-hydroxy-2-methylpropyl)-5-methyl-1H-pyrazol-4-yl)thiomorpholine 1,1-dioxide. LCMS (C31H37FN8O6S) (ES, m/z): 669 [M+H]+.
-
- To a 20 mL vial was added the mixture of rac-2-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-4-(1-(2-hydroxy-2-methylpropyl)-3-methyl-1H-pyrazol-4-yl)thiomorpholine 1,1-dioxide and rac-2-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-4-(1-(2-hydroxy-2-methylpropyl)-5-methyl-1H-pyrazol-4-yl)thiomorpholine 1,1-dioxide (48.1 mg, 0.0719 mmol) and TFA (0.96 mL). The mixture was stirred and heated at 50° C. for 1 h. The mixture was concentrated to a residue. The resulting residue was suspended in MeOH and filtered. The filtrate was concentrated to a residue that was purified by SFC (Chiral Technologies AS-H 21×250 mm column with 20% (MeOH w/0.1% NH4OH modifier) as co-solvent) to afford four peaks that were concentrated. Each peak was subsequently purified individually by preparative reversed-phase HPLC (Waters SunFire C18 OBD Prep Column, 19 mm×100 mm with MeCN/H2O (with 0.1% TFA) as eluent) to afford the final compounds, (R or S)-2-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-4-(1-(2-hydroxy-2-methylpropyl)-3-methyl-1H-pyrazol-4-yl)thiomorpholine 1,1-dioxide, and (S or R)-2-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-4-(1-(2-hydroxy-2-methylpropyl)-3-methyl-1H-pyrazol-4-yl)thiomorpholine 1,1-dioxide, and (R or S)-2-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-4-(1-(2-hydroxy-2-methylpropyl)-5-methyl-1H-pyrazol-4-yl)thiomorpholine 1,1-dioxide, and (S or R)-2-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-4-(1-(2-hydroxy-2-methylpropyl)-5-methyl-1H-pyrazol-4-yl)thiomorpholine 1,1-dioxide, corresponding to Example 142 (SFC peak 1), Example 143 (SFC peak 2), Example 144 (SFC peak 3), and Example 145 (SFC peak 4), respectively.
- For Example 142: LCMS (C22H27FN8O4S) (ES, m/z): 519 [M+H]+. 1H NMR (499 MHz, DMSO-d6) δ 7.91 (d, J=10.9 Hz, 1H), 7.88 (br s, 2H), 7.55 (s, 1H), 7.21 (d, J=7.8 Hz, 1H), 4.96 (dd, J=10.3, 3.5 Hz, 1H), 3.99 (s, 3H), 3.87-3.76 (m, 3H), 3.72-3.65 (m, 1H), 3.65-3.53 (m, 2H), 3.53-3.45 (m, 1H), 3.44-3.34 (m, 1H), 2.06 (s, 3H), 1.05 (s, 3H), 1.04 (s, 3H).
- For Example 143: LCMS (C22H27FN8O4S) (ES, m/z): 519 [M+H]+. 1H NMR (499 MHz, DMSO-d6) δ 7.91 (d, J=10.9 Hz, 1H), 7.88 (br s, 2H), 7.55 (s, 1H), 7.21 (d, J=7.8 Hz, 1H), 4.96 (dd, J=10.3, 3.5 Hz, 1H), 3.99 (s, 3H), 3.87-3.76 (m, 3H), 3.72-3.65 (m, 1H), 3.65-3.53 (m, 2H), 3.53-3.45 (m, 1H), 3.44-3.34 (m, 1H), 2.06 (s, 3H), 1.05 (s, 3H), 1.04 (s, 3H).
- For Example 144: LCMS (C22H27FN8O4S) (ES, m/z): 519 [M+H]+. 1H NMR (499 MHz, DMSO-d6) δ 7.89 (d, J=10.9 Hz, 1H), 7.86 (br s, 2H), 7.48 (s, 1H), 7.20 (d, J=7.8 Hz, 1H), 4.96 (dd, J=10.1, 3.4 Hz, 1H), 3.98 (s, 3H), 3.87-3.78 (m, 3H), 3.64-3.54 (m, 3H), 3.51-3.35 (m, 2H), 2.15 (s, 3H), 1.05 (s, 3H), 1.04 (s, 3H).
- For Example 145: LCMS (C22H27FN8O4S) (ES, m/z): 519 [M+H]+. 1H NMR (499 MHz, DMSO-d6) δ 7.89 (d, J=10.9 Hz, 1H), 7.86 (br s, 2H), 7.48 (s, 1H), 7.20 (d, J=7.8 Hz, 1H), 4.96 (dd, J=10.1, 3.4 Hz, 1H), 3.98 (s, 3H), 3.87-3.78 (m, 3H), 3.64-3.54 (m, 3H), 3.51-3.35 (m, 2H), 2.15 (s, 3H), 1.05 (s, 3H), 1.04 (s, 3H).
-
- Intermediate 124 (70.0 mg, 0.170 mmol) was resolved by chiral SFC (AD 250×30 mm column with MeOH (0.1% NH4OH modifier) as cosolvent) to afford (1R or 1S,3R or 3S)-3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-1-(1-ethyl-1H-pyrazol-4-yl)cyclohexan-1-ol (Example 146, first eluting peak) and (15 or 1R,3S or 3R)-3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-1-(1-ethyl-1H-pyrazol-4-yl)cyclohexan-1-ol (Example 147, second eluting peak).
- For Example 146: LCMS (C21H24FN7O2) (ES, m/z) [M+H]+: 426. 1H NMR (400 MHz, MeOD-d4) δ (ppm) 7.81 (s, 1H), 7.59-7.70 (m, 2H), 6.91 (br d, J=7.9 Hz, 1H), 4.20 (q, J=7.3 Hz, 2H), 3.88-3.99 (m, 3H), 2.89-3.01 (m, 1H), 2.75 (br d, J=13.2 Hz, 1H), 2.39 (br d, J=12.3 Hz, 1H), 1.97-2.13 (m, 2H), 1.88 (br dd, J=9.9, 3.3 Hz, 1H), 1.58-1.77 (m, 2H), 1.50-1.55 (m, 1H), 1.42-1.49 (m, 3H).
- For Example 147: LCMS (C21H24FN7O2) (ES, m/z) [M+H]+: 426. 1H NMR (400 MHz, MeOD-d4) δ (ppm) 7.71-7.87 (m, 2H), 7.64 (d, J=2.6 Hz, 1H), 6.96-7.18 (m, 1H), 4.20 (q, J=7.3 Hz, 2H), 3.97 (br d, J=13.2 Hz, 3H), 2.89-3.05 (m, 1H), 2.73 (br d, J=12.7 Hz, 1H), 2.40 (br d, J=12.7 Hz, 1H), 1.99-2.13 (m, 2H), 1.91 (br d, J=13.2 Hz, 1H), 1.62-1.79 (m, 2H), 1.52-1.59 (m, 1H), 1.47 (t, J=7.5 Hz, 3H).
-
- Intermediate 125 (50.0 mg, 0.120 mmol) was resolved by chiral SFC (AD 250×30 mm column with IPA (0.1% NH4OH modifier) as cosolvent) to afford (15 or 1R,3R or 35)-3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-1-(1-ethyl-1H-pyrazol-4-yl)cyclohexan-1-ol (Example 148, first eluting peak) and (15 or 1R,3R or 35)-3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-1-(1-ethyl-1H-pyrazol-4-yl)cyclohexan-1-ol (Example 149, second eluting peak).
- For Example 148: LCMS (C21H24 FN7O2) (ES, m/z) [M+H]+: 426. 1H NMR (400 MHz, MeOD-d4) δ (ppm) 7.78-7.94 (m, 1H), 7.60 (s, 1H), 7.50 (s, 1H), 7.01-7.23 (m, 1H), 4.14 (q, J=7.2 Hz, 2H), 3.99 (br s, 3H), 3.46-3.56 (m, 1H), 2.38 (br d, J=14.0 Hz, 1H), 1.92-2.25 (m, 4H), 1.63-1.85 (m, 3H), 1.42 (t, J=7.2 Hz, 3H).
- For Example 149: LCMS (C21H24 FN7O2) (ES, m/z) [M+H]+: 426. 1H NMR (400 MHz, MeOD-d4) δ (ppm) 7.81 (br s, 1H), 7.60 (s, 1H), 7.50 (s, 1H), 7.11 (br s, 1H), 4.09-4.20 (m, 2H), 3.96 (br s, 3H), 3.51 (br s, 1H), 2.38 (br d, J=13.6 Hz, 1H), 1.96-2.24 (m, 4H), 1.59-1.85 (m, 3H), 1.42 (t, J=7.2 Hz, 3H).
-
- To a 100 mL round bottom flask was added 2,6-di-tert-butylpyridine (11.1 ml, 49.4 mmol), ethyl 3-oxocyclohexane-1-carboxylate (6.32 ml, 35.3 mmol), and DCE (70.5 mL). The mixture was stirred and cooled at 0° C. To the mixture was added a 1 M solution in THF of Tf2O (45.8 mL, 45.8 mmol), dropwise over 5 min. The mixture was stirred for 30 min. The mixture was warmed to room temperature. After 2 h, the mixture was concentrated. To the resulting residue was added 1:1 DCM:hexanes (20 mL) and solids precipitated. The solids were removed by filtration. The filter cake was washed with 1:1 DCM:hexanes. The solvents of the filtrate were evaporated. The resulting residue was purified by silica gel chromatography with 0-100% EtOAc in hexanes as eluent, yielding ethyl 3-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-ene-1-carboxylate.
-
- To a 100 mL round bottom flask was added potassium acetate (3.96 g, 40.4 mmol), Pd(dppf)Cl2 (0.660 g, 0.808 mmol), bis(pinacolato)diboron (8.21 g, 32.3 mmol), and ethyl 3-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-ene-1-carboxylate (7.08 mL, 26.9 mmol). The flask was evacuated and refilled with nitrogen three times. To the flask was added DMA (40 mL). The mixture was stirred and heated at 90° C. for 16 h. The mixture was cooled to room temperature. The mixture was poured into a flask containing diethyl ether (150 mL). The mixture was stirred for 15 min. The solids were removed by filtration. The filtrate was washed with water (3×100 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered, and the solvents were evaporated. The resulting residue was purified by silica gel chromatography with 0-30% EtOAc in hexanes as eluent to afford ethyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-ene-1-carboxylate. LCMS (C15H25BO4) (ES, m/z) [M+H]+: 281.
-
- To a 100 mL flask was added Pd(dppf)Cl2 (0.708 g, 0.968 mmol), K3PO4 (15.4 g, 72.6 mmol), ethyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-ene-1-carboxylate (7.12 g, 25.4 mmol), and 1-(4-bromo-1H-pyrazol-1-yl)-2-methylpropan-2-ol (Intermediate 4) (5.30 g, 24.2 mmol). To the flask was added dioxane (60 mL) and water (12 mL). The mixture was sparged with nitrogen for 5 min. The mixture was stirred and heated at 90° C. for 2 h. The mixture was diluted in EtOAc (10 mL) and filtered through Celite® (diatomaceous earth) topped with anhydrous sodium sulfate. The solvents of the filtrate were evaporated. The resulting residue was purified by silica gel chromatography with 0-70% EtOAc in hexanes as eluent, to afford the racemate. The racemate was resolved by chiral SFC (ES Industries CCA 21×250 mm column, 15% (MeOH w/NH4OH modifier) as cosolvent) to afford ethyl (R or S)-3-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)cyclohex-3-ene-1-carboxylate (first eluting peak). LCMS (C16H24N2O3) (ES, m/z) [M+H]+: 293.
-
- To a 250 mL round bottom flask was added (R or S)-3-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)cyclohex-3-ene-1-carboxylate (933 mg, 3.19 mmol), cobalt (II) acetylacetonate hydrate (220 mg, 0.798 mmol), and THF (50 mL). To the mixture was added phenylsilane (1.18 mL, 9.57 mmol), and the mixture was stirred, open to air, at room temperature for 5 days. To the mixture was added a 1 M solution of TBAF (6.38 mL, 6.38 mmol) in THF. The mixture was stirred for 15 min. The solvents were evaporated. The resulting residue was purified by silica gel chromatography with 0-10% MeOH in DCM as eluent, to afford the trans-diastereomer ethyl (1R,3R or 1S,3S)-3-hydroxy-3-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)cyclohexane-1-carboxylate. LCMS (C16H26N2O4) (ES, m/z) [M+H]+: 311.
-
- To a 20 mL vial was added ethyl (1R,3R or 1S,3S)-3-hydroxy-3-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)cyclohexane-1-carboxylate (190 mg, 0.612 mmol), EtOH (1.5 mL), and hydrazine hydrate (0.210 ml, 3.67 mmol). The mixture was heated at 90° C. for 24 h. The solvents were evaporated to afford (1R,3R or 1S,3S)-3-hydroxy-3-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)cyclohexane-1-carbohydrazide. LCMS (C14H24N2O4) (ES, m/z) [M+H]+: 297.
-
- The asterisks (*) in the above scheme indicate chiral centers. To a 20 mL vial was added (1R,3R or 1S,3S)-3-hydroxy-3-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)cyclohexane-1-carbohydrazide (70.0 mg, 0.236 mmol), 2-((((2,4-dimethoxybenzyl)imino)methylene)amino)-5-fluoro-3-methoxybenzonitrile (105 mg, 0.307 mmol), dioxane (0.5 mL), and AcOH (7 μl, 0.12 mmol). The mixture was stirred and heated at 65° C. for 2 h. The solvents were evaporated. The residue was purified by silica gel chromatography with 0-100% EtOAc:EtOH (3:1) in hexanes as eluent to afford (1R,3R or 1S,35)-3-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-1-(1-(2-hydroxy-2-methylprop yl)-1H-pyrazol-4-yl)cyclohexan-1-ol. LCMS (C32H39N7O5) (ES, m/z) [M+H]+: 602.
-
- To a 20 mL vial was added DDQ (30.3 mg, 0.133 mmol) and DCM (1.0 mL). The mixture was cooled at 0° C. To the mixture was added water (0.05 mL). To the mixture was added (1R,3R or 1S,3S)-3-(5-((2,4-dimethoxybenzyl)amino)-7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-1-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)cyclohexan-1-ol (53.5 mg, 0.089 mmol) as a solution in DCM (1 mL). The mixture was stirred for 4 h. To the mixture was added 1 M aqueous KOH (20 mL), and then the mixture was extracted with DCM (2×20 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and the solvents of the filtrate were evaporated. The resulting residue was purified by silica gel chromatography with 0-100% EtOAc:EtOH (3:1) in hexane as eluent. The product was further purified by chiral SFC (Chiral Technologies OJ-H 21×250 mm column, with 20% (MeOH with NH4OH modifier) as cosolvent) to afford (1R,3R or 1S,3S)-3-(5-amino-7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-1-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)cyclohexan-1-ol (Example 150). LCMS (C23H29N7O3) (ES, m/z) [M+H]+: 452. 1H NMR (499 MHz, DMSO-d6) δ 7.73 (dd, J=8.0, 1.2 Hz, 3H), 7.56 (s, 1H), 7.39 (s, 1H), 7.29 (t, J=7.9 Hz, 1H), 7.24-7.10 (m, 1H), 4.81 (s, 1H), 4.65 (s, 1H), 3.95 (s, 2H), 3.90 (s, 3H), 3.48-3.40 (m, 1H), 2.22 (d, J=13.4 Hz, 1H), 2.09 (d, J=11.9 Hz, 1H), 1.98-1.84 (m, 3H), 1.73-1.58 (m, 3H), 1.16-0.89 (m, 9H).
-
- To a 20 mL vial was added (R)—N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-(piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine (Intermediate 82) (400 mg, 0.857 mmol), sodium tert-butoxide (330 mg, 3.43 mmol), 4-bromo-1-(2-methyl-1-((tetrahydro-2H-pyran-2-yl)oxy)propan-2-yl)-1H-pyrazole (Intermediate 151) (520 mg, 1.72 mmol), tBuXPhos-Pd G3 (272 mg, 0.343 mmol), and THF (5.7 mL). The mixture was purged with nitrogen for 5 min, sealed, and heated at 105° C. for 16 h. The reaction mixture was cooled to room temperature. To the mixture was added water (10 mL) and DCM (10 mL). The mixture was stirred for 10 min and filtered. The organic layer was collected with a phase separator. The solvents were evaporated. To the resulting residue was added TFA (3.8 mL, 49 mmol), and the mixture was heated at 50° C. for 3 h. The solvents were evaporated, and to the resulting residue was added DCM (10 mL), and a 7 M solution of ammonia in MeOH (1.07 mL, 7.52 mmol). The mixture was stirred for 1 h. The mixture was washed with water then brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvents of the filtrate were evaporated. The resulting residue was purified by silica gel chromatography column with 0-40% of MeOH in DCM as eluent to afford (R)-2-(4-(3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-1-ol (Example 151). LCMS (C22H27FN8O2) (ES, m/z): 455 [M+H]+. 1H NMR (600 MHz, Methanol-d4) δ 8.18 (s, 1H), 7.92 (d, J=10.7 Hz, 1H), 7.82 (s, 1H), 7.25 (d, J=7.6 Hz, 1H), 4.14 (dd, J=12.0, 3.5 Hz, 1H), 3.84 (dd, J=26.2, 11.7 Hz, 2H), 3.76 (s, 2H), 3.66 (dt, J=9.9, 5.9 Hz, 1H), 3.57-3.46 (m, 1H), 2.51-2.39 (m, 1H), 2.30-2.02 (m, 3H), 1.59 (s, 6H).
- The example compounds of the invention in the following Table 29 were prepared from the appropriate starting aryl halide and amine intermediates in a manner similar to that described for the preparation of Example 151.
-
TABLE 29 Observed Exam- Structure m/z [M + ple Name H]+ 152 469 (R)-4-(4-(3-(5-amino-9-fluoro-8-methoxy-[1,2,4] triazolo[1,5-c]quinazolin-2-yl)piperidin-1-yl)-1H- pyrazol-1-yl)-2-methylbutan-2-ol 153 491 (R)-1-(4-(3-(5-amino-8-(difluoromethoxy)-9-fluoro- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidin-1-yl)- 1H-pyrazol-1-yl)-2-methylpropan-2-ol 154 505 (R)-1-(4-(3-(5-amino-8-(difluoromethoxy)-9-fluoro- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidin-1-yl)-3- methyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol 155 483 racemic, trans-2-(4-(3-(5-amino-9-fluoro-8-methoxy- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-methylpiperidin- 1-yl)-3-methyl-1H-pyrazol-1-yl)-2-methylpropan-1-ol 156 469 racemic, trans-2-(4-(3-(5-amino-9-fluoro-8-methoxy- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-methylpiperidin- 1-yl)-1H-pyrazol-1-yl)-2-methylpropan-1-ol -
- A 20 mL microwave vial equipped with a stirbar was charged with rac, cis-N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-(5-methylpiperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine (Intermediate 83) (400 mg, 0.832 mmol) and THF (5.20 mL). To the mixture was added 1-(4-bromo-3-methyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol (Intermediate 24) (388 mg, 1.67 mmol), followed by tBuXPhos-Pd G3 (264 mg, 0.333 mmol) and sodium tert-butoxide (320 mg, 3.33 mmol). Nitrogen was bubbled through the mixture for 10 min. The vial was then sealed with a fresh cap and heated at 90° C. for 16 h. The reaction was cooled, quenched with saturated ammonium chloride (1 mL), and Celite was added. The biphasic mixture was filtered over Celite topped with anhydrous MgSO4, and the solvents of the filtrate were concentrated. The resulting residue was dissolved in TFA (3.2 mL, 42 mmol) and heated at 50° C. for 3 h. The reaction mixture was cooled, diluted with DCM, and quenched with saturated aqueous NaHCO3. The biphasic mixture was separated and the aqueous phase was further extracted with DCM. The organic layers were combined, dried over anhydrous MgSO4, filtered, and the solvents of the filtrate were concentrated. The resulting residue was purified by silica gel chromatography with 0-20% MeOH in DCM as eluent. The purified product was then subjected to chiral SFC separation (Chiral Technologies AD-H 21×250 mm column with 30% (IPA w/0.1% NH4OH modifier) as co-solvent), to afford 1-(4-((3R,5S or 3S,5R)-3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-methylpiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol (Example 157, first eluting peak) and 1-(4-((3S,5R or 3R,5S)-3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-methylpiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol (Example 158, second eluting peak).
- For Example 157: LCMS (C24H31FN8O2) (ES, m/z): 483 [M+H]+. 1H NMR (499 MHz, DMSO-d6) δ 7.87 (d, J=11.0 Hz, 1H), 7.69 (s, 2H), 7.34 (s, 1H), 7.18 (d, J=7.9 Hz, 1H), 4.61 (s, 1H), 3.97 (s, 3H), 3.83 (s, 2H), 3.46 (d, J=10.9 Hz, 1H), 3.28 (d, J=11.8 Hz, 1H), 3.13 (d, J=8.6 Hz, 1H), 2.64 (t, J=11.3 Hz, 1H), 2.22 (d, J=13.4 Hz, 1H), 2.16 (t, J=11.1 Hz, 1H), 2.11 (s, 3H), 1.94 (s, 1H), 1.38 (q, J=12.3 Hz, 1H), 1.03 (d, J=3.1 Hz, 6H), 0.97 (d, J=6.6 Hz, 3H). For Example 158: LCMS (C24H31FN8O2) (ES, m/z): 483 [M+H]+. 1H NMR (499 MHz, DMSO-d6) δ 7.87 (d, J=11.0 Hz, 1H), 7.69 (s, 2H), 7.34 (s, 1H), 7.18 (d, J=7.8 Hz, 1H), 4.61 (s, 1H), 3.97 (s, 3H), 3.83 (s, 2H), 3.47 (d, J=8.4 Hz, 1H), 3.29 (s, 1H), 3.13 (d, J=8.0 Hz, 1H), 2.64 (t, J=11.3 Hz, 1H), 2.22 (d, J=12.5 Hz, 1H), 2.16 (t, J=11.0 Hz, 1H), 2.11 (s, 3H), 1.96 (s, 1H), 1.38 (q, J=12.4 Hz, 1H), 1.03 (d, J=3.1 Hz, 6H), 0.97 (d, J=6.6 Hz, 3H).
- The example compounds of the invention in the following Table 30 were prepared from the appropriate starting amine and aryl halide in a manner similar to that described for the preparation of Example 157 and Example 158, where the resulting isomeric mixture of the corresponding final compounds were separated by SFC.
-
TABLE 30 Observed m/z Exam- Structure [M + ple Name SFC Conditions H]+ 159 Peak 1; Cellulose-2 30 × 250 mm column with 5-15% (MeOH w/0.05% DEA modifier) as co-solvent 469 1-(4-(3R,5S or 3S,5R)-3-(5-amino-9-fluoro-7- methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5- methylpiperidin-1-yl)-1H-pyrazol-1-yl)-2- methylpropan-2-ol 160 Peak 2; Cellulose-2 30 × 250 mm column with 5-15% (MeOH w/0.05% DEA modifier) as co-solvent 469 1-(4-((3S,5R or 3R,5S)-3-(5-amino-9-fluoro-7- methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5- methylpiperidin-1-yl)-1H-pyrazol-1-yl)-2- methylpropan-2-ol 161 Peak 1; Cellulose-3 4.6 × 150 mm column with 5-15% (MeOH w/0.05% DEA modifier) as co-solvent 483 1-(4-((3R,5S or 3S,5R)-3-(5-amino-9-fluoro-7- methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5- methylpiperidin-1-yl)-3-methyl-1H-pyrazol-1-yl)- 2-methylpropan-2-ol 162 Peak 2; Cellulose-3 4.6 × 150 mm column with 5-15% (MeOH w/0.05% DEA modifier) as co-solvent 483 1-(4-((3S,5R or 3R,5S)-3-(5-amino-9-fluoro-7- methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5- methylpiperidin-1-yl)-3-methyl-1H-pyrazol-1-yl)- 2-methylpropan-2-ol 163 Peak 1; Chiral Technologies AS-H 21 × 250 mm column with 25% (MeOH w/ 0.1% NH4OH modifier) as co-solvent 457 1-(4-((3R,5S or 3S,5R)-3-(5-amino-7,9-difluoro- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5- methylpiperidin-1-yl)-1H-pyrazol-1-yl)-2- methylpropan-2-ol 164 Peak 2; Chiral Technologies AS-H 21 × 250 mm column with 25% (MeOH w/ 0.1% NH4OH modifier) as co-solvent 457 1-(4-((3S,5R or 3R,5S)-3-(5-amino-7,9-difluoro- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5- methylpiperidin-1-yl)-1H-pyrazol-1-yl)-2- methylpropan-2-ol 165 Peak 1; Lux-4 21 × 250 mm column with 40% (MeOH w/0.1% NH4OH modifier) as co-solvent 469 2-(4-((3R,5S or 3S,5R)-3-(5-amino-9-fluoro-7- methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5- methylpiperidin-1-yl)-1H-pyrazol-1-yl)-2- methylpropan-1-ol 166 Peak 2; Lux-4 21 × 250 mm column with 40% (MeOH w/0.1% NH4OH modifier) as co-solvent 469 2-(4-((3S,5R or 3R,5S)-3-(5-amino-9-fluoro-7- methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)- 5-methylpiperidin-1-yl)-1H-pyrazol-1-yl)- 2-methylpropan-1-ol 167 Peak 1; Lux-4 21 × 250 mm column with 30% (MeOH w/0.1% NH4OH modifier) as co-solvent 471 1-(4-((3R,5S or 3S,5R)-3-(5-amino-7,9-difluoro- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5- methylpiperidin-1-yl)-3-methyl-1H-pyrazol-1-yl)- 2-methylpropan-2-ol 168 Peak 2; Lux-4 21 × 250 mm column with 30% (MeOH w/0.1% NH4OH modifier) as co-solvent 471 1-(4-((3S,5R or 3R,5S)-3-(5-amino-7,9-difluoro- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5- methylpiperidin-1-yl)-3-methyl-1H-pyrazol-1-yl)- 2-methylpropan-2-ol 169 Peak 1; Chiralpak AD- 3 4.6 × 150 mm column with 0-40% (IPA w/0.05% DEA modifier) as co- solvent 483 2-(4-((3R,5S or 3S,5R)-3-(5-amino-9-fluoro-8- methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5- methylpiperidin-1-yl)-3-methyl-1H-pyrazol-1-yl)- 2-methylpropan-1-ol 170 Peak 2; Chiralpak AD- 3 4.6 × 150 mm column with 0-40% (IPA w/0.05% DEA modifier) as co- solvent 483 2-(4-((3S,5R or 3R,5S)-3-(5-amino-9-fluoro-8- methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5- methylpiperidin-1-yl)-3-methyl-1H-pyrazol-1-yl)- 2-methylpropan-1-ol 171 Peak 1; Chiralpak AD- 3 4.6 × 150 mm column with 5-40% (EtOH w/0.05% DEA modifier) as co- solvent 469 2-(4-((3R,5S or 3S,5R)-3-(5-amino-9-fluoro-8- methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5- methylpiperidin-1-yl)-1H-pyrazol-1-yl)-2- methylpropan-1-ol 172 Peak 2; Chiralpak AD- 3 4.6 × 150 mm column with 5-40% (EtOH w/0.05% DEA modifier) as co- solvent 469 2-(4-((3S,5R or 3R,5S)-3-(5-amino-9-fluoro-8- methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5- methylpiperidin-1-yl)-1H-pyrazol-1-yl)-2- methylpropan-1-ol 173 Peak 1; ES Industries CCA 21 × 250 mm column with 25% (MeOH w/0.1% NH4OH modifier) as co-solvent 483 1-(4-((3R,5S or 3S,5R)-3-(5-amino-9-fluoro-7- methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5- methylpiperidin-1-yl)-5-methyl-1H-pyrazol-1-yl)- 2-methylpropan-2-ol 174 Peak 2; ES Industries CCA 21 × 250 mm column with 25% (MeOH w/0.1% NH4OH modifier) as co-solvent 483 1-(4-((3S,5R or 3R,5S)-3-(5-amino-9-fluoro-7- methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5- methylpiperidin-1-yl)-5-methyl-1H-pyrazol-1-yl)- 2-methylpropan-2-ol 175 Peak 1; Chiralpak AD- 3 4.6 × 150 mm column with 5-40% (MeOH w/0.05% DEA modifier) as co-solvent 483 2-(4-((3R,5S or 3S,5R)-3-(5-amino-9-fluoro-7- methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5- methylpiperidin-1-yl)-3-methyl-1H-pyrazol-1-yl)- 2-methylpropan-1-ol 176 Peak 2; Chiralpak AD- 3 4.6 × 150 mm column with 5-40% (MeOH w/0.05% DEA modifier) as co-solvent 483 2-(4-((3S,5R or 3R,5S)-3-(5-amino-9-fluoro-7- methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5- methylpiperidin-1-yl)-3-methyl-1H-pyrazol-1-yl)-2- methylpropan-1-ol 177 Peak 1; Chiralpak AD- 3 4.6 × 150 mm column with 5-40% (IPA w/0.05% DEA modifier) as co-solvent 471 2-(4-((3R,5S or 3S,5R)-3-(5-amino-7,9-difluoro- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5- methylpiperidin-1-yl)-3-methyl-1H-pyrazol-1-yl)- 2-methylpropan-1-ol 178 Peak 2; Chiralpak AD- 3 4.6 × 150 mm column with 5-40% (IPA w/0.05% DEA modifier) as co-solvent 471 2-(4-((3S,5R or 3R,5S)-3-(5-amino-7,9-difluoro- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5- methylpiperidin-1-yl)-3-methyl-1H-pyrazol-1-yl)- 2-methylpropan-1-ol 179 Peak 1; Chiral Technologies OJ-H 21 × 250 mm colum with 20% (MeOH w/0.1% NH4OH modifier) as co-solvent 457 2-(4-((3S,5S or 3R,5R)-3-(5-amino-7,9-difluoro- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5- methylpiperidin-1-yl)-1H-pyrazol-1-yl)-2- methylpropan-1-ol 180 Peak 2; Chiral Technologies OJ-H 21 × 250 mm column with 20% (MeOH w/0.1% NH4OH modifier) as co-solvent 457 2-(4-((3R,5R or 3S,5S)-3-(5-amino-7,9-difluoro- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5- methylpiperidin-1-yl)-1H-pyrazol-1-yl)-2- methylpropan-1-ol 181 Peak 1; Chiral Technologies OJ-H 21 × 250 mm column with 20% (MeOH w/0.1% NH4OH modifier) as co-solvent 457 1-(4-((3S,5S or 3R,5R)-3-(5-amino-7,9-difluoro- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5- methylpiperidin-1-yl)-1H-pyrazol-1-yl)-2- methylpropan-2-ol 182 Peak 2; Chiral Technologies OJ-H 21 × 250 mm column with 20% (MeOH w/0.1% NH4OH modifier) as co-solvent 457 1-(4-((3R,5R or 3S,5S)-3-(5-amino-7,9-difluoro- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5- methylpiperidin-1-yl)-1H-pyrazol-1-yl)-2- methylpropan-2-ol 183 Peak 1; Chiralpak AD- 3 4.6 × 150 mm column with 5-40% (IPA w/0.05% DEA modifier) as co-solvent 469 (R or S)-1-(4-((R)-3-(5-amino-9-fluoro-8- methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2- yl)piperidin-1-yl)-1H-pyrazol-1-yl)-2- methylbutan-2-ol 184 Peak 2; Chiralpak AD- 3 4.6 × 150 mm column with 5-40% (IPA w/0.05% DEA modifier) as co-solvent 469 (S or R)-1-(4-((R)-3-(5-amino-9-fluoro-8- methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2- yl)piperidin-1-yl)-1H-pyrazol-1-yl)-2- methylbutan-2-ol 185 Peak 1; ES Industries CCA 21 × 250 mm column with 30% (MeOH w/0.1% NH4OH modifier) as co-solvent 455 (2S,3S or 2R,3R)-3-(4-((R)-3-(5-amino-9-fluoro- 7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2- yl)piperidin-1-yl)-1H-pyrazol-1-yl)butan-2-ol 186 Peak 2; ES Industries CCA 21 × 250 mm column with 30% (MeOH w/0.1% NH4OH modifier) as co-solvent 455 (2R,3R or 2S,3S)-3-(4-((R)-3-(5-amino-9-fluoro- 7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2- yl)piperidin-1-yl)-1H-pyrazol-1-yl)butan-2-ol 187 Peak 1; Chiral Technologies AS-H 21 × 250 mm column with 30% (MeOH w/ 0.1% NH4OH modifier) as co-solvent 455 (2S,3S or 2R,3R)-3-(4-((R)-3-(5-amino-9-fluoro- 8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2- yl)piperidin-1-yl)-1H-pyrazol-1-yl)butan-2-ol 188 Peak 2; Chiral Technologies AS-H 21 × 250 mm column with 30% (MeOH w/ 0.1% NH4OH modifier) as co-solvent 455 (2R,3R or 2S,3S)-3-(4-((R)-3-(5-amino-9-fluoro- 8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2- yl)piperidin-1-yl)-1H-pyrazol-1-yl)butan-2-ol 189 Peak 1; ES Industries CCA 21 × 250 mm column with 15% (MeOH w/0.1% NH4OH modifier) as co-solvent 469 (2S,3S or 2R,3R)-3-(4-((R)-3-(5-amino-9-fluoro- 7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2- yl)piperidin-1-yl)-3-methyl-1H-pyrazol-1- yl)butan-2-ol 190 Peak 2; ES Industries CCA 21 × 250 mm column with 15% (MeOH w/0.1% NH4OH modifier) as co-solvent 469 (2R,3R or 2S,3S)-3-(4-((R)-3-(5-amino-9-fluoro- 7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2- yl)piperidin-1-yl)-3-methyl-1H-pyrazol-1- yl)butan-2-ol 191 Peak 1; Chiral Technologies AD-H 21 × 250 mm column with 30% (MeOH w/ 0.1% NH4OH modifier) as co- solvent 457 (2S,3S or 2R,3R)-3-(4-((R)-3-(5-amino-7,9- difluoro-[1,2,4]triazolo[1,5-c]quinazolin-2- yl)piperidin-1-yl)-3-methyl-1H-pyrazol-1- yl)butan-2-ol 192 Peak 2; Chiral Technologies AD-H 21 × 250 mm column with 30% (MeOH w/ 0.1% NH4OH modifier) as co-solvent 457 (2R,3R or 2S,3S)-3-(4-((R)-3-(5-amino-7,9- difluoro-[1,2,4]triazolo[1,5-c]quinazolin-2- yl)piperidin-1-yl)-3-methyl-1H-pyrazol-1- yl)butan-2-ol 193 Peak 1; Chiral Technologies AD-H 21 × 250 mm column with 25% (MeOH w/ 0.1% NH4OH modifier) as co-solvent 469 (2S,3S or 2R,3R)-3-(4-((R)-3-(5-amino-9-fluoro- 7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2- yl)piperidin-1-yl)-5-methyl-1H-pyrazol-1- yl)butan-2-ol 194 Peak 2; Chiral Technologies AD-H 21 × 250 mm column with 25% (MeOH w/ 0.1% NH4OH modifier) as co-solvent 469 (2R,3R or 2S,3S)-3-(4-((R)-3-(5-amino-9-fluoro- 7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2- yl)piperidin-1-yl)-5-methyl-1H-pyrazol-1- yl)butan-2-ol 195 Peak 1; Chiral Technologies IG 21 × 250 mm column with 35% (MeOH w/0.1% NH4OH modifier) as co-solvent 469 (2S,3S or 2R,3R)-3-(4-((R)-3-(5-amino-9-fluoro- 8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2- yl)piperidin-1-yl)-5-methyl-1H-pyrazol-1- yl)butan-2-ol 196 Peak 2; Chiral Technologies IG 21 × 250 mm column with 35% (MeOH w/0.1% NH4OH modifier) as co-solvent 469 (2R,3R or 2S,3S)-3-(4-((R)-3-(5-amino-9-fluoro- 8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2- yl)piperidin-1-yl)-5-methyl-1H-pyrazol-1- yl)butan-2-ol 197 Peak 1; Chiralpak AS- 3 4.6 × 150 mm column with 5-40% (IPA w/0.05% DEA modifier) as co-solvent 443 (2S,3S or 2R,3R)-3-(4-((R)-3-(5-amino-7,9- difluoro-[1,2,4]triazolo[1,5-c]quinazolin-2- yl)piperidin-1-yl)-1H-pyrazol-1-yl)butan-2-ol 198 Peak 2; Chiralpak AS- 3 4.6 × 150 mm column with 5-40% (IPA w/0.05% DEA modifier) as co- solvent 443 (2R,3R or 2S,3S)-3-(4-((R)-3-(5-amino-7,9- difluoro-[1,2,4]triazolo[1,5-c]quinazolin-2- yl)piperidin-1-yl)-1H-pyrazol-1-yl)butan-2-ol 199 Peak 1; Chiral Technologies OJ-H 21 × 250 mm column with 15% (MeOH w/0.1% NH4OH modifier) as co-solvent 455 (2R,3S or 2S,3R)-3-(4-((R)-3-(5-amino-9-fluoro- 8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2- yl)piperidin-1-yl)-1H-pyrazol-1-yl)butan-2-ol 200 Peak 2; Chiral Technologies OJ-H 21 × 250 mm column with 15% (MeOH w/0.1% NH4OH modifier) as co-solvent 455 (2S,3R or 2R,3S)-3-(4-((R)-3-(5-amino-9-fluoro- 8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2- yl)piperidin-1-yl)-1H-pyrazol-1-yl)butan-2-ol 201 Peak 1; Chiral Technologies AD-H 21 × 250 mm column with 35% (MeOH w/ 0.1% NH4OH modifier) as co-solvent 455 (2R,3S or 2S,3R)-3-(4-((R)-3-(5-amino-9-fluoro- 7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2- yl)piperidin-1-yl)-1H-pyrazol-1-yl)butan-2-ol 202 Peak 2; Chiral Technologies AD-H 21 × 250 mm column with 35% (MeOH w/ 0.1% NH4OH modifier) as co-solvent 455 (2S,3R or 2R,3S)-3-(4-((R)-3-(5-amino-9-fluoro- 7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2- yl)piperidin-1-yl)-1H-pyrazol-1-yl)butan-2-ol 203 Peak 1; Chiralpak AS- 3 4.6 × 100 mm column with 0-40% (IPA w/0.05% DEA modifier) as co-solvent 443 (2R,3S or 2S,3R)-3-(4-((R)-3-(5-amino-7,9- difluoro-[1,2,4]triazolo[1,5-c]quinazolin-2- yl)piperidin-1-yl)-1H-pyrazol-1-yl)butan-2-ol 204 Peak 2; Chiralpak AS- 3 4.6 × 100 mm column with 0-40% (IPA w/0.05% DEA modifier) as co-solvent 443 (2S,3R or 2R,3S)-3-(4-((R)-3-(5-amino-7,9- difluoro-[1,2,4]triazolo[1,5-c]quinazolin-2- yl)piperidin-1-yl)-1H-pyrazol-1-yl)butan-2-ol 205 Peak 1; Chiralpak AD- 3 4.6 × 100 mm column with 5-40% (IPA w/0.05% DEA modifier) as co- solvent. Then Peak 1; Chiral Technologies AD-H 21 × 250 mm column with 20% (IPA w/0.1% NH4OH modifier) as co-solvent 497 (R or S)-3-(4-((3R,5S or 3S,5R)-3-(5-amino-9- fluoro-7-methoxy-[1,2,4[triazolo[1,5-c]quinazolin- 2-yl)-5-methylpiperidin-1-yl)-3-methyl-1H- pyrazol-1-yl)-3-methylbutan-2-ol 206 Peak 1; Chiralpak AD- 3 4.6 × 100 mm column with 5-40% (IPA w/0.05% DEA modifier) as co- solvent. Then Peak 2; Chiral Technologies AD-H 21 × 250 mm column with 20% (IPA w/0.1% NH4OH modifier) as co-solvent 497 (S or R)-3-(4-((3R,5S or 3S,5R)-3-(5-amino-9- fluoro-7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin- 2-yl)-5-methylpiperidin-1-yl)-3-methyl-1H- pyrazol-1-yl)-3-methylbutan-2-ol 207 Peak 2; Chiralpak AD- 3 4.6 × 100 mm column with 5-40% (IPA w/0.05% DEA modifier) as co-solvent. 497 (R or S)-3-(4-((3S,5R or 3R,5S)-3-(5-amino-9- fluoro-7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin- 2-yl)-5-methylpiperidin-1-yl)-3-methyl-1H- pyrazol-1-yl)-3-methylbutan-2-ol 208 Peak 1; ES Industries CC4 21 × 250 mm column with 35% (MeOH w/0.1% NH4OH modifier) as co-solvent. Then Peak 1; ES Industries CCA 21 × 250 mm column with 15% (MeOH w/ 0.1% NH4OH modifier) as co-solvent 483 (2S,3S or 2R,3R)-3-(4-((3R,5S or 3S,5R)-3-(5- amino-9-fluoro-8-methoxy-[1,2,4[triazolo[1,5- c]quinazolin-2-yl)-5-methylpiperidin-1-yl)-3- methyl-1H-pyrazol-1-yl)butan-2-ol 209 Peak 1; ES Industries CC4 21 × 250 mm column with 35% (MeOH w/0.1% NH4OH modifier) as co-solvent. Then Peak 2; ES Industries CCA 21 × 250 mm column with 15% (MeOH w/ 0.1% NH4OH modifier) as co-solvent 483 (2R,3R or 2S,3S)-3-(4-((3R,5S or 3S,5R)-3-(5- amino-9-fluoro-8-methoxy-[1,2,4[triazolo[1,5- c]quinazolin-2-yl)-5-methylpiperidin-1-yl)-3- methyl-1H-pyrazol-1-yl)butan-2-ol 210 Peak 2; ES Industries CC4 21 × 250 mm column with 35% (MeOH w/0.1% NH4OH modifier) as co-solvent. 483 (2R,3R or 2S,3S)-3-(4-((3S,5R or 3R,5S)-3-(5- amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5- c]quinazolin-2-yl)-5-methylpiperidin-1-yl)-3- methyl-1H-pyrazol-1-yl)butan-2-ol 211 Peak 3; ES Industries CC4 21 × 250 mm column with 35% (MeOH w/0.1% NH4OH modifier) as co-solvent. 483 (2S,3S or 2R,3R)-3-(4-((3S,5R or 3R,5S)-3-(5- amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5- c]quinazolin-2-yl)-5-methylpiperidin-1-yl)-3- methyl-1H-pyrazol-1-yl)butan-2-ol 212 Peak 1; Chiral Technologies AD-H 30 × 250 mm column with 5-40% (IPA w/ 0.05% DEA modifier) as co-solvent. 471 (2S,3S or 2R,3R)-3-(4-((3R,5S or 3S,5R)-3-(5- amino-7,9-difluoro-[1,2,4]triazolo[1,5- c]quinazolin-2-yl)-5-methylpiperidin-1-yl)-3- methyl-1H-pyrazol-1-yl)butan-2-ol 213 Peak 2; Chiral Technologies AD-H 30 × 250 mm column with 5-40% (IPA w/ 0.05% DEA modifier) as co-solvent. 471 (2R,3R or 2S,3S)-3-(4-((3R,5S or 3S,5R)-3-(5- amino-7,9-difluoro-[1,2,4]triazolo[1,5- c]quinazolin-2-yl)-5-methylpiperidin-1-yl)-3- methyl-1H-pyrazol-1-yl)butan-2-ol 214 Peak 3; Chiral Technologies AD-H 30 × 250 mm column with 5-40% (IPA w/ 0.05% DEA modifier) as co-solvent. 471 (2R,3R or 2S,3S)-3-(4-((3S,5R or 3R,5S)-3-(5- amino-7,9-difluoro-[1,2,4]triazolo[1,5- c]quinazolin-2-yl)-5-methylpiperidin-1-yl)-3- methyl-1H-pyrazol-1-yl)butan-2-ol 215 Peak 4; Chiral Technologies AD-H 30 × 250 mm column with 5-40% (IPA w/ 0.05% DEA modifier) as co-solvent. 471 (2S,3S or 2R,3R)-3-(4-((3S,5R or 3R,5S)-3-(5- amino-7,9-difluoro-[1,2,4]triazolo[1,5- c]quinazolin-2-yl)-5-methylpiperidin-1-yl)-3- methyl-1H-pyrazol-1-yl)butan-2-ol 216 Peak 1; IG 50 × 250 mm column with 5- 40% (EtOH w/0.05% DEA modifier) as co- solvent. 471 (2S,3S or 2R,3R)-3-(4-((3R,5S or 3S,5R)-3-(5- amino-7,9-difluoro-[1,2,4]triazolo[1,5- c]quinazolin-2-yl)-5-methylpiperidin-1-yl)-5- methyl-1H-pyrazol-1-yl)butan-2-ol 217 Peak 2; IG 50 × 250 mm column with 5- 40% (EtOH w/0.05% DEA modifier) as co- solvent. 471 (2R,3R or 2S,3S)-3-(4-((3R,5S or 3S,5R)-3-(5- amino-7,9-difluoro-[1,2,4]triazolo[1,5- c]quinazolin-2-yl)-5-methylpiperidin-1-yl)-5- methyl-1H-pyrazol-1-yl)butan-2-ol 218 Peak 3; IG 50 × 250 mm column with 5- 40% (EtOH w/0.05% DEA modifier) as co-solvent. 471 (2R,3R or 2S,3S)-3-(4-((3S,5R or 3R,5S)-3-(5- amino-7,9-difluoro-[1,2,4]triazolo[1,5- c]quinazolin-2-yl)-5-methylpiperidin-1-yl)-5- methyl-1H-pyrazol-1-yl)butan-2-ol 219 Peak 4; IG 50 × 250 mm column with 5- 40% (EtOH w/0.05% DEA modifier) as co- solvent. 471 (2S,3S or 2R,3R)-3-(4-((3S,5R or 3R,5S)-3-(5- amino-7,9-difluoro-[1,2,4]triazolo[1,5- c]quinazolin-2-yl)-5-methylpiperidin-1-yl)-5- methyl-1H-pyrazol-1-yl)butan-2-ol 220 Peak 1; Chiralpak AD- 3 4.6 × 150 mm column with 5-40% (IPA w/0.05% DEA modifier) as co-solvent. 483 (2S,3S or 2R,3R)-3-(4-((3R,5S or 3S,5R)-3-(5- amino-9-fluoro-7-methoxy-[1,2,4]triazolo[1,5- c]quinazolin-2-yl)-5-methylpiperidin-1-yl)-5- methyl-1H-pyrazol-1-yl)butan-2-ol 221 Peak 2; Chiralpak AD- 3 4.6 × 150 mm column with 5-40% (IPA w/0.05% DEA modifier) as co-solvent. 483 (2R,3R or 2S,3S)-3-(4-((3R,5S or 3S,5R)-3-(5- amino-9-fluoro-7-methoxy-[1,2,4]triazolo[1,5- c]quinazolin-2-yl)-5-methylpiperidin-1-yl)-5- methyl-1H-pyrazol-1-yl)butan-2-ol 222 Peak 3; Chiralpak AD- 3 4.6 × 150 mm column with 5-40% (IPA w/0.05% DEA modifier) as co-solvent 483 (2R,3R or 2S,3S)-3-(4-((3S,5R or 3R,5S)-3-(5- amino-9-fluoro-7-methoxy-[1,2,4]triazolo[1,5- c]quinazolin-2-yl)-5-methylpiperidin-1-yl)-5- methyl-1H-pyrazol-1-yl)butan-2-ol 223 Peak 4; Chiralpak AD- 3 4.6 × 150 mm column with 5-40% (IPA w/0.05% DEA modifier) as co-solvent. 483 (2S,3S or 2R,3R)-3-(4-((3S,5R or 3R,5S)-3-(5- amino-9-fluoro-7-methoxy-[1,2,4]triazolo[1,5- c]quinazolin-2-yl)-5-methylpiperidin-1-yl)-5- methyl-1H-pyrazol-1-yl)butan-2-ol 224 Peak 1; Chiral Technologies AD-H 30 × 250 mm column with 5-40% (EtOH w/ 0.05% DEA modifier) as co-solvent. Then Peak 1; Chiral Technologies AD-H 30 × 250 mm column with 5-40% (IPA w/ 0.05% DEA modifier) as co-solvent. 483 (2S,3S or 2R,3R)-3-(4-((3R,5S or 3S,5R)-3-(5- amino-9-fluoro-7-methoxy-[1,2,4[triazolo[1,5- c]quinazolin-2-yl)-5-methylpiperidin-1-yl)-3- methyl-1H-pyrazol-1-yl)butan-2-ol 225 Peak 1; Chiral Technologies AD-H 30 × 250 mm column with 5-40% (EtOH w/ 0.05% DEA modifier) as co-solvent. Then Peak 2; Chiral Technologies AD-H 30 × 250 mm column with 5-40% (IPA w/ 0.05% DEA modifier) as co-solvent. 483 (2R,3R or 2S,3S)-3-(4-((3R,5S or 3S,5R)-3-(5- amino-9-fluoro-7-methoxy-[1,2,4[triazolo[1,5- c]quinazolin-2-yl)-5-methylpiperidin-1-yl)-3- methyl-1H-pyrazol-1-yl)butan-2-ol 226 Peak 2; Chiral Technologies AD-H 30 × 250 mm column with 5-40% (EtOH w/ 0.05% DEA modifier) as co-solvent. 483 (2R,3R or 2S,3S)-3-(4-((3S,5R or 3R,5S)-3-(5- amino-9-fluoro-7-methoxy-[1,2,4]triazolo[1,5- c]quinazolin-2-yl)-5-methylpiperidin-1-yl)-3- methyl-1H-pyrazol-1-yl)butan-2-ol 227 Peak 3; Chiral Technologies AD-H 30 × 250 mm column with 5-40% (EtOH w/ 0.05% DEA modifier) as co-solvent. 483 (2S,3S or 2R,3R)-3-(4-((3S,5R or 3R,5S)-3-(5- amino-9-fluoro-7-methoxy-[1,2,4]triazolo[1,5- c]quinazolin-2-yl)-5-methylpiperidin-1-yl)-3-methyl- 1H-pyrazol-1-yl)butan-2-ol -
- To solution of N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-((3R,6S and 3S,6R)-6-methyl-1-(1H-pyrazol-4-yl)piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine (Intermediate 177) (530 mg, 0.970 mmol) in DMF (10 mL) was added cis-2,3-dimethyloxirane (846 μl, 9.70 mmol) and cesium carbonate (1.26 g, 3.88 mmol). The mixture was stirred and heated at 125° C. for 5 h. The mixture was cooled to room temperature, and the mixture was diluted with water (20 mL) and ethyl acetate (20 mL). The biphasic mixture was separated and the aqueous phase was further extracted with ethyl acetate (20 mL). The combined organic layers were then washed with water (2×20 mL) and brine (1×20 mL). The organic layer was dried over anhydrous MgSO4, filtered, and the solvents were evaporated. The residue was purified by silica gel chromatography with 0-20% MeOH in DCM as eluent to afford the intermediate mixture of diastereomers of (2S,3S and 2R,3R)-3-(4-((2S,5R or 2R,5S)-5-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-1H-pyrazol-1-yl)butan-2-ol.
- To a 20 mL vial was added 3-(4-(5-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-1H-pyrazol-1-yl)butan-2-ol (475 mg, 0.768 mmol) and TFA (1.77 mL 23.0 mmol). The mixture was stirred and heated at 50° C. for 3 h. The mixture was cooled at room temperature, and the solvents were evaporated. The residue was dissolved in MeOH (10 mL) and quenched with a 7 M solution of ammonia in MeOH (1.10 mL, 7.68 mmol). The mixture was stirred for 20 minutes. The mixture was filtered, rinsing the solids with MeOH, and the filtrate was concentrated. The residue was suspended in DCM and filtered to remove remaining ammonium salts. The filtrate was was loaded directly onto a silica gel column, eluting with 0-15% MeOH in DCM to afford a mixture of isomers. The mixture was submitted for chiral SFC separation (Phenomenex Lux-2 21×250 mm column with 45% (MeOH w/0.1% NH4OH modifier) as co-solvent), to afford a mixture of Example 228 and Example 229 (peak 1), (2R,3R or 2S,3S)-3-(4-((2R,5S or 2S,5R)-5-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-1H-pyrazol-1-yl)butan-2-ol (Example 230, peak 2) and (2R,3R or 2S,3S)-3-(4-((2S,5R or 2R,5S)-5-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-1H-pyrazol-1-yl)butan-2-ol (Example 231, peak 3). The mixture obtained in peak 1 was further purified by SFC separation (Chiral Technologies AS-H 21×250 mm column with 20% (MeOH w/0.1% NH4OH modifier) as co-solvent), to afford (2S,3S or 2R,3R)-3-(4-((2S,5R or 2R,5S)-5-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-1H-pyrazol-1-yl)butan-2-ol (Example 228, peak 1) and (2S,3S or 2R,3R)-3-(4-((2R,5S or 2S,5R)-5-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-1H-pyrazol-1-yl)butan-2-ol (Example 229, peak 2).
- For Example 228: LCMS (C23H29FN8O2) (ES, m/z): 469 [M+H]+. 1H NMR (499 MHz, DMSO-d6) δ 7.90 (d, J=10.6 Hz, 1H), 7.73 (s, 2H), 7.22 (s, 1H), 7.19 (d, J=7.4 Hz, 1H), 7.12 (s, 1H), 4.73 (d, J=5.0 Hz, 1H), 4.13-4.05 (m, 1H), 3.98 (s, 3H), 3.88-3.78 (m, 1H), 3.70 (s, 1H), 3.19 (s, 1H), 3.10 (t, J=11.5 Hz, 1H), 2.01 (d, J=21.4 Hz, 3H), 1.70 (d, J=9.1 Hz, 1H), 1.34 (d, J=6.9 Hz, 3H), 1.03 (d, J=6.6 Hz, 3H), 0.92 (d, J=6.1 Hz, 3H).
- For Example 229: LCMS (C23H29FN8O2) (ES, m/z): 469 [M+H]+. 1H NMR (499 MHz, DMSO-d6) δ 7.90 (d, J=8.2 Hz, 1H), 7.73 (s, 2H), 7.25-7.21 (m, 1H), 7.19 (d, J=4.8 Hz, 1H), 7.12 (d, J=2.9 Hz, 1H), 4.72 (s, 1H), 4.09 (s, 1H), 3.98 (d, J=2.7 Hz, 3H), 3.83 (s, 1H), 3.70 (s, 1H), 3.19 (s, 1H), 3.10 (t, J=10.5 Hz, 1H), 1.99 (s, 3H), 1.72 (s, 1H), 1.43-1.30 (m, 3H), 1.03 (d, J=3.4 Hz, 3H), 0.92 (d, J=3.0 Hz, 3H).
- For Example 230: LCMS (C23H29FN8O2) (ES, m/z): 469 [M+H]+. 1H NMR (499 MHz, DMSO-d6) δ 7.90 (d, J=11.0 Hz, 1H), 7.72 (s, 2H), 7.22 (s, 1H), 7.18 (d, J=7.8 Hz, 1H), 7.11 (s, 1H), 4.77-4.64 (m, 1H), 4.14-4.04 (m, 1H), 4.02-3.94 (m, 3H), 3.88-3.78 (m, 1H), 3.71 (d, J=9.9 Hz, 1H), 3.18 (dd, J=6.4, 4.4 Hz, 1H), 3.09 (t, J=11.4 Hz, 1H), 2.01 (d, J=22.2 Hz, 3H), 1.70 (d, J=10.4 Hz, 1H), 1.38-1.31 (m, 3H), 1.03 (d, J=6.4 Hz, 3H), 0.95-0.89 (m, 3H).
- For Example 231: LCMS (C23H29FN8O2) (ES, m/z): 469 [M+H]+. 1H NMR (499 MHz, DMSO-d6) δ 7.90 (d, J=9.6 Hz, 1H), 7.73 (s, 2H), 7.22 (s, 1H), 7.19 (d, J=6.7 Hz, 1H), 7.12 (s, 1H), 4.73 (d, J=3.3 Hz, 1H), 4.15-4.03 (m, 1H), 3.98 (s, 3H), 3.83 (d, J=5.2 Hz, 1H), 3.70 (s, 1H), 3.19 (s, 1H), 3.10 (t, J=11.0 Hz, 1H), 2.01 (d, J=21.8 Hz, 3H), 1.70 (d, J=9.6 Hz, 1H), 1.33 (d, J=5.7 Hz, 3H), 1.03 (d, J=5.4 Hz, 3H), 0.92 (d, J=5.0 Hz, 3H).
- The example compounds of the invention in the following Table 31 were prepared in a manner similar to that described for the preparation of Example 228-231 from the appropriate starting materials and intermediates, where the resulting isomeric mixture of the corresponding final compounds were separated by SFC.
-
TABLE 31 Observed Structure m/z Example Name SFC Conditions [M + H]+ 232 Peak 1 (mixture of Example 232 and Example 233); Phenomenex Lux-2 21 × 250 mm column with 45% (MeOH w/0.1% NH4OH modifier) as co- solvent. Then Peak 1; Chiral Technologies AS-H 21 × 250 mm column with 20% (MeOH w/0.1% NH4OH modifier) as co-solvent. 457 (2S,3S or 2R,3R)-3-(4-((2S,5R or 2R,5S)-5-(5- amino-7,9-difluoro-[1,2,4]triazolo[1,5-c]quinazolin- 2-yl)-2-methylpiperidin-1-yl)-1H-pyrazol-1- yl)butan-2-ol 233 Peak 1 (mixture of Example 232 and Example 233); Phenomenex Lux-2 21 × 250 mm column with 45% (MeOH w/0.1% NH4OH modifier) as co- solvent. Then Peak 2; Chiral Technologies AS-H 21 × 250 mm column with 20% (MeOH w/0.1% NH4OH modifier) as co-solvent. 457 (2R,3R or 2S,3S)-3-(4-((2S,5R or 2R,5S)-5-(5- amino-7,9-difluoro-[1,2,4]triazolo[1,5-c]quinazolin- 2-yl)-2-methylpiperidin-1-yl)-1H-pyrazol-1- yl)butan-2-ol 234 Peak 2; Phenomenex Lux-2 21 × 250 mm column with 45% (MeOH w/0.1% NH4OH modifier) as co-solvent. 457 (2R,3R or 2S,3S)-3-(4-((2R,5S or 2S,5R)-5-(5- amino-7,9-difluoro-[1,2,4]triazolo[1,5-c]quinazolin- 2-yl)-2-methylpiperidin-1-yl)-1H-pyrazol-1- yl)butan-2-ol 235 Peak 3; Phenomenex Lux-2 21 × 250 mm column with 45% (MeOH w/0.1% NH4OH modifier) as co-solvent. 457 (2S,3S or 2R,3R)-3-(4-((2R,5S or 2S,5R)-5-(5-amino- 7,9-difluoro-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2- methylpiperidin-1-yl)-1H-pyrazol-1-yl)butan-2-ol 236 Peak 1; Chiral Technologies AD-H 21 × 250 mm column with 40% (MeOH w/0.1% NH4OH modifier) as co- solvent. 469 (2S,3R or 2R,3S)-3-(4-((2S,5R or 2R,5S)-5-(5-amino- 9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2- yl)-2-methylpiperidin-1-yl)-1H-pyrazol-1-yl)butan-2-ol 237 Peak 2; Chiral Technologies AD-H 21 × 250 mm column with 40% (MeOH w/0.1% NH4OH modifier) as co- solvent. 469 (2R,3S or 2S,3R)-3-(4-((2S,5R or 2R,5S)-5-(5-amino- 9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2- yl)-2-methylpiperidin-1-yl)-1H-pyrazol-1-yl)butan-2-ol 238 Peak 1; Phenomenex Lux-3 21 × 250 mm column with 15% (MeOH w/0.1% NH4OH modifier) as co-solvent. 469 (2S,3R or 2R,3S)-3-(4-((2R,5S or 2S,5R)-5-(5-amino-9- fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)- 2-methylpiperidin-1-yl)-1H-pyrazol-1-yl)butan-2-ol 239 Peak 2; Phenomenex Lux-3 21 × 250 mm column with 15% (MeOH w/0.1% NH4OH modifier) as co-solvent. 469 (2R,3S or 2S,3R)-3-(4-((2R,5S or 2S,5R)-5-(5-amino-9- fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)- 2-methylpiperidin-1-yl)-1H-pyrazol-1-yl)butan-2-ol 240 Peak 1; Chiral Technologies AS-H 21 × 250 mm column with 25% (MeOH w/0.1% NH4OH modifier) as co- solvent. 469 (R or S)-1-(4-((2S,5R or 2R,5S)-5-(5-amino-9-fluoro-8- methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2- methylpiperidin-1-yl)-1H-pyrazol-1-yl)propan-2-ol 241 Peak 2; Chiral Technologies AS-H 21 × 250 mm column with 25% (MeOH w/0.1% NH4OH modifier) as co- solvent. 469 (S or R)-1-(4-((2S,5R or 2R,5S)-5-(5-amino-9-fluoro-8- methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2- methylpiperidin-1-yl)-1H-pyrazol-1-yl)propan-2-ol -
- A 5 mL microwave vial equipped with a stirbar was charged with (R)—N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-(piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine (Intermediate 82) (100 mg, 0.214 mmol) and THF (1.3 mL). To the mixture was added 3-(4-bromo-1H-pyrazol-1-yl)-3-methylbutan-2-one (Intermediate 137) (99.0 mg, 0.429 mmol), followed by tBuXPhos-Pd G3 (85.0 mg, 0.107 mmol) and sodium tert-butoxide (82.0 mg, 0.857 mmol). Nitrogen was bubbled through the mixture for 10 min. The vial was then sealed with a fresh cap and heated at 105° C. for 16 h. The reaction mixture was cooled to room temperature, and to the mixture was added water (10 mL) and DCM (10 mL). The mixture was stirred for 10 min and filtered. The organic layer was collected and concentrated. To the resulting residue was added TFA (826 μL, 10.7 mmol), and the mixture was heated at 50° C. for 3 h. The solvents were evaporated. The resulting residue was dissolved in MeOH (5 mL), and to the mixture was added a 7 M solution of ammonia in MeOH (1.53 mL, 10.7 mmol). The mixture was stirred for 30 min and filtered. The solids were washed with methanol. The filtrate was concentrated. The residue was dissolved in DCM, and the resulting solution was washed with water. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvents were evaporated. The resulting residue was purified by silica gel chromatography with 5-30% MeOH in DCM as eluent to afford (R)-3-(4-(3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidin-1-yl)-1H-pyrazol-1-yl)-3-methylbutan-2-one LCMS (C23H27FN8O2) (ES, m/z): 467 [M+H]+. Step 2: (R or S)-3-(4-((R)-3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidin-1-yl)-1H-pyrazol-1-yl)-3-methylbutan-2-ol and (S or R)-3-(4-((R)-3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidin-1-yl)-1H-pyrazol-1-yl)-3-methylbutan-2-ol
- To a solution of (R)-3-(4-(3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidin-1-yl)-1H-pyrazol-1-yl)-3-methylbutan-2-one (49.0 mg, 0.105 mmol) in EtOH (1 mL) was added NaBH4 (11.9 mg, 0.315 mmol), and the mixture was stirred at room temperature for 1 h. The solvents were evaporated. To the resulting residue was added DCM, and the mixture was washed with water. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvents of the filtrate were evaporated to afford a mixture of isomers. The mixture was submitted for SFC chiral separation (Chiral Technologies IA 21×250 mm column with 45% (MeOH w/0.1% NH4OH modifier) as co-solvent), to afford (R or S)-3-(4-((R)-3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidin-1-yl)-1H-pyrazol-1-yl)-3-methylbutan-2-ol (Example 242, peak 1) and (S or R)-3-(4-((R)-3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidin-1-yl)-1H-pyrazol-1-yl)-3-methylbutan-2-ol (Example 243, peak 2).
- For Example 242: LCMS (C23H29FN8O2) (ES, m/z): 469 [M+H]+. 1H NMR (499 MHz, DMSO-d6) δ 7.88 (dd, J=10.9, 2.3 Hz, 1H), 7.71 (s, 2H), 7.42-7.34 (m, 1H), 7.24-7.07 (m, 2H), 4.80 (s, 1H), 3.97 (d, J=2.2 Hz, 3H), 3.82 (s, 1H), 3.62 (d, J=11.3 Hz, 1H), 3.36 (s, 1H), 3.24 (s, 1H), 2.82 (t, J=10.2 Hz, 1H), 2.15 (s, 1H), 1.80 (d, J=40.9 Hz, 3H), 1.48-1.42 (m, 3H), 1.42-1.34 (m, 3H), 0.73 (dd, J=6.1, 2.3 Hz, 3H).
- For Example 243: LCMS (C23H29FN8O2) (ES, m/z): 469 [M+H]+. 1H NMR (499 MHz, DMSO-d6) δ 7.93-7.83 (m, 1H), 7.71 (s, 2H), 7.38 (s, 1H), 7.22-7.10 (m, 2H), 4.81 (s, 1H), 4.01-3.95 (m, 3H), 3.82 (s, 1H), 3.62 (d, J=10.8 Hz, 1H), 3.37 (s, 1H), 3.24 (s, 1H), 2.82 (t, J=11.3 Hz, 1H), 2.55 (d, J=9.7 Hz, 1H), 2.15 (s, 1H), 1.90-1.67 (m, 3H), 1.45 (s, 3H), 1.39 (s, 3H), 0.76-0.67 (m, 3H).
- The example compounds of the invention in the following Table 32 were prepared in a manner similar to that described for the preparation of Example 242 and Example 243 from the appropriate starting amine and aryl halide, where the resulting isomeric mixture of the corresponding final compounds were separated by SFC.
-
TABLE 32 Observed Structure m/z Example Name SFC Conditions [M + H]+ 244 Peak 1; Chiral Technologies IA 21 × 250 mm column with 40% (MeOH w/0.1% NH4OH modifier) as co- solvent 469 (R or S)-3-(4-((R)-3-(5-amino-9-fluoro-7-methoxy- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidin-1-yl)- 1H-pyrazol-1-yl)-3-methylbutan-2-ol 245 Peak 2; Chiral Technologies IA 21 × 250 mm column with 40% (MeOH w/0.1% NH4OH modifier) as co- solvent 469 (S or R)-3-(4-((R)-3-(5-amino-9-fluoro-7-methoxy- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidin-1-yl)- 1H-pyrazol-1-yl)-3-methylbutan-2-ol 246 Peak 1; ES Industries CCA 21 × 250 mm column with 35% (MeOH w/0.1% NH4OH modifier) as co-solvent 457 (R or S)-3-(4-((R)-3-(5-amino-7,9-difluoro- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidin-1-yl)- 1H-pyrazol-1-yl)-3-methylbutan-2-ol 247 Peak 2; ES Industries CCA 21 × 250 mm column with 35% (MeOH w/0.1% NH4OH modifier) as co-solvent 457 (S or R)-3-(4-((R)-3-(5-amino-7,9-difluoro- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidin-1-yl)- 1H-pyrazol-1-yl)-3-methylbutan-2-ol -
- To a solution of 1-(1-(1,3-dihydroxy-2-methylpropan-2-yl)-1H-pyrazol-4-yl)-6-methylpiperidine-3-carbohydrazide (105 mg, 0.336 mmol) (Intermediate 166) in DMF (1 mL) was added AcOH (9.63 μl, 0.168 mmol), 2-((((3,4-dimethylbenzyl)imino)methylene)amino)-3,5-difluorobenzonitrile (Intermediate 37) (100 mg, 0.336 mmol) at 50° C. under an atmosphere of nitrogen. The mixture was stirred and heated at 50° C. for 16 h. The mixture was cooled, diluted with water (20 mL), and extracted with EtOAc (2×20 mL). The organic layer was dried over anhydrous Na2SO4, filtered and the solvents were evaporated. The resulting residue was purified by preparative silica gel TLC with 10% MeOH in DCM as eluent to afford 2-(4-(5-(5-((2,4-dimethoxybenzyl)amino)-7,9-difluoro-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropane-1,3-diol. LCMS (C31H36F2N8O4) (ES, m/z): 623 [M+H]+.
- Step 2: 2-(4-(5-(5-amino-7,9-difluoro-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-1H-pyrazol-1-yl)-3-hydroxy-2-methylpropyl 2,2,2-trifluoroacetate To a solution of 2-(4-(5-(5-((2,4-dimethoxybenzyl)amino)-7,9-difluoro-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropane-1,3-diol (60 mg, 0.096 mmol) in DCM (2 mL) was added TFA (2.0 mL, 26 mmol) at 10° C. under a nitrogen atmosphere. The mixture was stirred at 10° C. for 16 h. The solvents were evaporated to afford the crude product of 2-(4-(5-(5-amino-7,9-difluoro-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-1H-pyrazol-1-yl)-3-hydroxy-2-methylpropyl 2,2,2-trifluoroacetate, which was used in the next step without any further purification. LCMS (C24H25F5N8O3) (ES, m/z): 569 [M+H]+.
- To a solution of 2-(4-(5-(5-amino-7,9-difluoro-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-1H-pyrazol-1-yl)-3-hydroxy-2-methylpropyl 2,2,2-trifluoroacetate (40 mg, 0.070 mmol) in MeOH (2 mL) was added Na2CO3 (7.5 mg, 0.070 mmol) at 10° C. under a nitrogen atmosphere. The mixture was stirred at 10° C. for 1 h. The solvents were evaporated to afford a mixture of isomers. The mixture was submitted for SFC chiral separation (Chiralpak AD-3 4.6×150 mm column with 5-40% (MeOH w/0.05% DEA modifier) as co-solvent), to afford 2-(4-((2S,5R or 2R,5S)-5-(5-amino-7,9-difluoro-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropane-1,3-diol (Example 248, peak 1) and 2-(4-((2R,5S or 2S,5R)-5-(5-amino-7,9-difluoro-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropane-1,3-diol (Example 249, peak 2).
- For Example 248: LCMS (C22H26F2N8O2) (ES, m/z): 473 [M+H]+. 1H NMR (500 MHz, methanol-d4) δ=7.71 (br dd, J=1.3, 6.8 Hz, 1H), 7.38-7.26 (m, 2H), 7.22 (s, 1H), 3.78-3.68 (m, 4H), 3.64 (br dd, J=3.8, 6.1 Hz, 1H), 3.41 (br d, J=8.2 Hz, 1H), 2.96 (s, 1H), 2.82 (s, 1H), 2.06-1.99 (m, 2H), 1.98 (s, 1H), 1.73 (br dd, J=3.1, 12.7 Hz, 1H), 1.42 (s, 3H), 1.03 (d, J=6.7 Hz, 3H).
- For Example 249: LCMS (C22H26F2N8O2) (ES, m/z): 473 [M+H]+. 1H NMR (500 MHz, methanol-d4) δ=7.84 (br s, 1H), 7.53-7.41 (m, 2H), 7.36 (br s, 1H), 3.93-3.79 (m, 4H), 3.78 (br s, 1H), 3.55 (br s, 1H), 2.22 (br s, 1H), 2.18-2.09 (m, 2H), 1.87 (br d, J=10.1 Hz, 1H), 1.54 (s, 3H), 1.31 (s, 2H), 1.16 (d, J=6.6 Hz, 3H).
- The example compounds of the invention in the following Table 33 were prepared in a manner similar to that described for the preparation of Example 248 and Example 249 from the appropriate starting hydrazide, where the resulting isomeric mixture of the corresponding final compounds were separated by SFC.
-
TABLE 33 Observed Structure m/z Example Name SFC Conditions [M + H]+ 250 Peak 1; Chiralpak AD-3 4.6 × 150 mm column with 5-40% (MeOH w/0.05% DEA modifier) as co-solvent 485 2-(4-((2S,5R or 2R,5S)-5-(5-amino-9-fluoro-8-methoxy- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin- 1-yl)-1H-pyrazol-1-yl)-2-methylpropane-1,3-diol 251 Peak 2; Chiralpak AD-3 4.6 × 150 mm column with 5-40% (MeOH w/0.05% DEA modifier) as co-solvent. 485 2-(4-((2R,5S or 2S,5R)-5-(5-amino-9-fluoro-8-methoxy- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin- 1-yl)-1H-pyrazol-1-yl)-2-methylpropane-1,3-diol 252 Peak 2; Chiralcel OJ-3 4.6 × 100 mm column with 5-40% (EtOH w/0.05% DEA modifier) as co-solvent. Then Peak 1; Chiralpak AD-3 4.6 × 150 mm column with 40% (MeOH w/0.05% DEA modifier) as co-solvent. 485 (R or S)-2-(4-((2S,5R or 2R,5S)-5-(5-amino-9-fluoro-8-methoxy- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)- 1H-pyrazol-1-yl)-2-methylpropane-1,2-diol 253 Peak 2; Chiralcel OJ-3 4.6 × 100 mm column with 5-40% (EtOH w/0.05% DEA modifier) as co-solvent. Then Peak 2; Chiralpak AD-3 4.6 × 150 mm column with 40% (MeOH w/0.05% DEA modifier) as co-solvent. 485 (S or R)-2-(4-((2S,5R or 2R,5S)-5-(5-amino-9-fluoro-8-methoxy- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)- 1H-pyrazol-1-yl)-2-methylpropane-1,2-diol 254 Peak 3; Chiralcel OJ-3 4.6 × 100 mm column with 5-40% (EtOH w/0.05% DEA modifier) as co-solvent. 485 (R or S)-2-(4-((2R,5S or 2S,5R)-5-(5-amino-9-fluoro-8-methoxy- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)- 1H-pyrazol-1-yl)-2-methylpropane-1,2-diol 255 Peak 4; Chiralcel OJ-3 4.6 × 100 mm column with 5-40% (EtOH w/0.05% DEA modifier) as co-solvent. 485 (S or R)-2-(4-((2R,5S or 2S,5R)-5-(5-amino-9-fluoro-8-methoxy- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)- 1H-pyrazol-1-yl)-2-methylpropane-1,2-diol 256 Peak 3; Cellulose 2 4.6 × 100 mm column with 40% (MeOH w/0.05% DEA modifier) as co- solvent. Then Peak 1; Chiralpak AS-3 4.6 × 150 mm column with 5-40% (IPA w/0.05% DEA modifier) as co- solvent. 473 (R or S)-2-(4-((2S,5R or 2R,5S)-5-(5-amino-7,9-difluoro- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1- yl)-1H-pyrazol-1-yl)-2-methylpropane-1,2-diol 257 Peak 3; Cellulose 2 4.6 × 100 mm column with 40% (MeOH w/0.05% DEA modifier) as co- solvent. Then Peak 2; Chiralpak AS-3 4.6 × 150 mm column with 5-40% (IPA w/0.05% DEA modifier) as co- solvent. 473 (S or R)-2-(4-((2S,5R or 2R,5S)-5-(5-amino-7,9-difluoro- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1- yl)-1H-pyrazol-1-yl)-2-methylpropane-1,2-diol 258 Peak 4; Cellulose 2 4.6 × 100 mm column with 40% (MeOH w/0.05% DEA modifier) as co- solvent. 473 (R or S)-2-(4-((2R,5S or 2S,5R)-5-(5-amino-7,9-difluoro- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1- yl)-1H-pyrazol-1-yl)-2-methylpropane-1,2-diol 259 Peak 5; Cellulose 2 4.6 × 100 mm column with 40% (MeOH w/0.05% DEA modifier) as co- solvent. 473 (S or R)-2-(4-((2R,5S or 2S,5R)-5-(5-amino-7,9-difluoro- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1- yl)-1H-pyrazol-1-yl)-2-methylpropane-1,2-diol 260 Peak 1; Chiralpak AS-3 4.6 × 100 mm column with 5-40% (MeOH w/0.05% DEA modifier) as co- solvent. 487 (R or S)-2-(4-((2R,5S or 2S,5R)-5-(5-amino-7,9- difluoro-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2- methylpiperidin-1-yl)-1H-pyrazol-1-yl)-2- methylpropane-1,2-diol 261 Peak 2; Chiralpak AS-3 4.6 × 100 mm column with 5-40% (MeOH w/0.05% DEA modifier) as co-solvent. 487 (S or R)-2-(4-((2R,5S or 2S,5R)-5-(5-amino-7,9- difluoro-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2- methylpiperidin-1-yl)-1H-pyrazol-1-yl)-2- methylpropane-1,2-diol 262 Peak 1; ES Industries CC4 21 × 250 mm column with 40% (MeOH w/0.1% NH4OH modifier) as co-solvent. 468 2-((3R,6S or 3S,6R)-1-(1-(2-amino-2-methylpropyl)-1H-pyrazol-4- yl)-6-methylpiperidin-3-yl)-9-fluoro-8-methoxy- [1,2,4]triazolo[1,5-c]quinazolin-5-amine 263 Peak 2; ES Industries CC4 21 × 250 mm column with 40% (MeOH w/0.1% NH4OH modifier) as co-solvent. 468 2-((3S,6R or 3R,6S)-1-(1-(2-amino-2-methylpropyl)-1H-pyrazol-4- yl)-6-methylpiperidin-3-yl)-9-fluoro-8-methoxy- [1,2,4]triazolo[1,5-c]quinazolin-5-amine 264 Peak 1; ES Industries CCA 21 × 250 mm column with 25% (MeOH w/0.1% NH4OH modifier) as co-solvent 483 (R or S)-3-(4-((2S,5R or 2R,5S)-5-(5-amino-9-fluoro- 8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2- methylpiperidin-1-yl)-1H-pyrazol-1-yl)-3- methylbutan-2-ol 265 Peak 2 (mixture of Example 265 and Example 266); ES Industries CCA 21 × 250 mm column with 25% (MeOH w/0.1% NH4OH modifier) as co-solvent. Then Peak 1; Lux-4 21 × 250 mm column with 35% (MeOH w/0.1% NH4OH modifier) 483 (S or R)-3-(4-((2S,5R or 2R,5S)-5-(5-amino-9-fluoro- 8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2- methylpiperidin-1-yl)-1H-pyrazol-1-yl)-3- methylbutan-2-ol 266 Peak 2 (mixture of Example 265 and Example 266); ES Industries CCA 21 × 250 mm column with 25% (MeOH w/0.1% NH4OH modifier) as co-solvent. Then Peak 2; Lux-4 21 × 250 mm column with 35% (MeOH w/0.1% NH4OH modifier) 483 (R or S)-3-(4-((2R,5S or 2S,5R)-5-(5-amino-9-fluoro- 8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)- 2-methylpiperidin-1-yl)-1H-pyrazol-1-yl)-3- methylbutan-2-ol 267 Peak 3; ES Industries CCA 21 × 250 mm column with 25% (MeOH w/0.1% NH4OH modifier) as co-solvent 483 (S or R)-3-(4-((2R,5S or 2S,5R)-5-(5-amino-9-fluoro- 8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)- 2-methylpiperidin-1-yl)-1H-pyrazol-1-yl)-3- methylbutan-2-ol 268 Peak 1 (mixture of Example 268 and Example 269); Chiral Technologies OJ-H 21 × 250 mm column with 10% (MeOH w/0.1% NH4OH modifier) as co- solvent. Then peak 1; ID 21 × 250 mm column with 35% (MeOH w/0.1% NH4OH modifier) as co-solvent. 483 (R or S)-3-(4-((2S,5R or 2R,5S)-5-(5-amino-9-fluoro- 7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)- 2-methylpiperidin-1-yl)-1H-pyrazol-1-yl)-3- methylbutan-2-ol 269 Peak 1 (mixture of Example 268 and Example 269); Chiral Technologies OJ-H 21 × 250 mm column with 10% (MeOH w/0.1% NH4OH modifier) as co- solvent. Then peak 2; ID 21 × 250 mm column with 35% (MeOH w/0.1% NH4OH modifier) as co-solvent. 483 (S or R)-3-(4-((2S,5R or 2R,5S)-5-(5-amino-9-fluoro- 7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)- 2-methylpiperidin-1-yl)-1H-pyrazol-1-yl)-3- methylbutan-2-ol 270 Peak 2; Chiral Technologies OJ-H 21 × 250 mm column with 10% (MeOH w/0.1% NH4OH modifier) as co- solvent. 483 (R or S)-3-(4-((2R,5S or 2S,5R)-5-(5-amino-9-fluoro- 7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)- 2-methylpiperidin-1-yl)-1H-pyrazol-1-yl)-3- methylbutan-2-ol 271 Peak 3; Chiral Technologies OJ-H 21 × 250 mm column with 10% (MeOH w/0.1% NH4OH modifier) as co- solvent. 483 (S or R)-3-(4-((2R,5S or 2S,5R)-5-(5-amino-9-fluoro- 7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)- 2-methylpiperidin-1-yl)-1H-pyrazol-1-yl)-3- methylbutan-2-ol 272 Peak 1; Chiralpak AS- 3 4.6 × 150 mm column with 5-40% (EtOH w/0.05% DEA modifier) as co- solvent. 467 1-((4-((2S,5R or 2R,5S)-5-(5-amino-9-fluoro-8- methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2- methylpiperidin-1-yl)-1H-pyrazol-1- yl)methyl)cyclopropan-1-ol 273 Peak 2; Chiralpak AS- 3 4.6 × 150 mm column with 5-40% (EtOH w/0.05% DEA modifier) as co- solvent. 467 1-((4-((2R,5S or 2S,5R)-5-(5-amino-9-fluoro-8- methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2- methylpiperidin-1-yl)-1H-pyrazol-1- yl)methyl)cyclopropan-1-ol 274 Peak 2; Chiral Technologies AD-H 21 × 250 mm column with 30% (MeOH w/ 0.1% NH4OH modifier) as co- solvent. 483 1-((4-((3R,5S or 3S,5R)-3-(5-amino-9-fluoro-8- methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5- methylpiperidin-1-yl)-1H-pyrazol-1- yl)-2-methylpropan-2-ol 275 Peak 3; Chiral Technologies AD-H 21 × 250 mm column with 30% (MeOH w/ 0.1% NH4OH modifier) as co- solvent. 483 1-(4-((3S,5R or 3R,5S)-3-(5-amino-9-fluoro-8- methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5- methylpiperidin-1-yl)-5-methyl-1H-pyrazol-1- yl)-2-methylpropan-2-ol - The IC50 values reported for each of the compounds of the invention shown in the table below were measured in accordance with the methods described below.
- The A2a receptor affinity binding assay measured the amount of binding of a tritiated ligand with high affinity for the A2a adenosine receptor to membranes made from HEK293 or CHO cells recombinantly expressing the human A2a adenosine receptor, in the presence of varying concentrations of a compound of the invention. In each assay, the tested compounds of the invention were solubilized in 100% DMSO and further diluted in 100% DMSO to generate, typically, a 10-point titration at half-log intervals such that the final assay concentrations did not exceed 10 μM of compound or 1% DMSO.
- 148 μL (5 μg/mL) membranes (Perkin Elmer, Cat. No. RBHA2aM400UA) and 2 μL compounds of the invention to be tested (test compound) were transferred to individual wells of a 96-well polypropylene assay plate and incubated for 15 to 30 minutes at room temperature. [3H] SCH58261 ((7-(2-phenylethyl)-5-amino-2-(2-furyl)-pyrazolo-[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine)) was diluted in assay buffer (50 mM Tris pH 7.4, 10 mM MgCl2, 0.005% Tween20) to a concentration of 4 nM and 50 μL transferred to each well of the assay plate. To define total and non-specific binding, wells containing 1% DMSO and 1 μM ZM241385 (Tocris Bioscience, Cat. No. 1036) respectively, were also included. The assay plate was incubated at room temperature for 60 minutes with agitation. Using a FilterMate Harvester® (Perkin Elmer), the contents of the assay plate were filtered through a UniFilter-96® PEI coated plate (Perkin Elmer Cat. No. 6005274 or 6005277). Filtering was achieved by aspirating the contents of the assay plate for 5 seconds, then washing and aspirating the contents three times with ice-cooled wash buffer (50 mM Tris-HCl pH 7.4, 150 mM NaCl) and allowing the vacuum manifold to dry the plate for 30 seconds. The filter plate was incubated for at least 1 hour at 55° C. and allowed to dry. The bottom of the filter plate was sealed with backing tape. 40 μL Ultima Gold™ (Perkin Elmer, Cat. No. 6013329) was added to each well of the filter plate and the top of the plate was sealed with TopSeal-A PLUS® clear plate seal (Perkin Elmer, Cat. No. 6050185). The plate was incubated for at least 20 minutes, and then the amount of radioactivity remaining in each well was determined using a TopCount® (Perkin Elmer) scintillation counter. After normalization to total and non-specific binding, the percent effect at each compound concentration was calculated. The plot of percent effect versus the log of compound concentration was analyzed electronically using a 4-parameter logistic fit based on the Levenberg-Marquardt algorithm to generate IC50 values.
- The reported affinity of the compounds of the invention for the human A2b adenosine receptor was determined experimentally using a radioligand filtration binding assay. This assay measures the amount of binding of a tritiated proprietary A2b receptor antagonist, in the presence and absence of a compound of the invention, to membranes made from HEK293 cells recombinantly expressing the human A2b adenosine receptor (Perkin Elmer, Cat. No. ES-013-C).
- To perform the assay, compounds of the invention to be tested were first solubilized in 100% DMSO and further diluted in 100% DMSO to generate, typically, a 10-point titration at half-log intervals such that the final assay concentrations did not exceed 10 μM of compound or 1% DMSO. 148 μL (135 μg/mL) membranes and 2 μL test compounds were transferred to individual wells of a 96-well polypropylene assay plate and incubated for 15 to 30 minutes at room temperature with agitation. Tritiated radioligand was diluted to a concentration of 14 nM in assay buffer (phosphate buffered saline without Magnesium and Calcium, pH 7.4; GE Healthcare Life Sciences, Cat. No. SH30256.01) and then 50 μL of the solution were transferred to each well of the assay plate. To define total and non-specific binding, wells containing 1% DMSO and 20 μM N-ethylcarboxamidoadenosine (Tocris Bioscience, Cat. No. 1691) respectively, were also included. The wells of the assay plate were incubated at room temperature for 60 minutes with agitation, then filtered using a FilterMate Harvester® (Perkin Elmer) or similar equipment through a UniFilter-96® PEI coated plate (Perkin Elmer Cat. No. 6005274 or 6005277). Filtering was achieved by aspirating the contents of the assay plate for 5 seconds, then washing and aspirating the contents three times with ice-cooled wash buffer (assay buffer supplemented with 0.0025% Brij58) and allowing the vacuum manifold to dry the plate for 30 seconds. The filter plate was incubated for at least 1 hour at 55° C. and allowed to dry. The bottom of the filter plate was then sealed with backing tape. 40 μL Ultima Gold™ (Perkin Elmer, Cat. No. 6013329) was added to each well of the filter plate and the top of the plate was sealed with TopSeal-A PLUS® clear plate seal (Perkin Elmer, Cat. No. 6050185). The plates were then incubated for at least 20 minutes, and then the amount of radioactivity remaining in each well was determined using a TopCount® (Perkin Elmer) scintillation counter. After normalization to total and non-specific binding, the percent effect at each compound concentration was calculated. The plot of percent effect versus the log of compound concentration was analyzed electronically using a 4-parameter logistic fit based on the Levenberg-Marquardt algorithm to generate IC50 values.
-
Example A2A IC50 binding (nM) A2B IC50 binding (nM) 1 7.5 554.2 2 3.7 9.4 3 1.5 180.4 4 4.6 2.6 5 3.3 1.6 6 2.0 85.9 7 3.7 104.1 8 4.5 149.3 9 0.5 136.0 10 3.5 63.4 11 0.5 56.0 12 1.7 75.0 13 0.7 72.6 14 3.0 224.9 15 38.4 905.2 16 0.8 426.0 17 1.7 433.9 18 0.7 13.5 19 0.7 87.3 20 5.8 163 21 0.3 514.6 22 8.6 27.6 23 2.0 15.9 24 13.8 480.5 25 0.6 61.7 26 3.9 48.7 27 1.8 860.8 28 2.8 76.3 29 1.5 301.1 30 0.4 97.9 31 1.7 94.8 32 0.5 6.9 33 3.6 17.5 34 1.4 29.7 35 0.6 12.2 36 1.6 93.0 37 1.1 468.1 38 16.9 182.4 39 1.1 43.3 40 1.2 9.2 41 1.2 42.8 42 4.3 475.7 43 0.7 3.4 44 1.3 20.4 45 1.8 150.4 46 0.6 86.4 47 8.2 284.2 48 0.6 17.6 49 0.3 2.7 50 18.3 1889 51 21.0 2079 52 18.3 3006 53 44.1 4239 54 3.3 194.6 55 10.6 500.2 56 1.8 846.5 57 48.3 85.6 58 13.6 136.2 59 67.0 4744 60 31.4 5862 61 5.0 99.0 62 146.1 382.8 63 242.2 2431 64 1.0 555.3 65 1.2 227.9 66 0.6 957.1 67 44% Inh. 31% Inh. @ 1000 nM @ 10000 nM 68 181.4 31% Inh. @ 10000 nM 69 2.6 561.4 70 0.6 786.5 71 35.6 43% Inh. @ 10000 nM 72 2.0 484 73 436.0 5124 74 0.9 153.3 75 56.9 54% Inh. @ 10000 nM 76 256.4 34% Inh. @ 10000 nM 77 0.4 107.9 78 0.9 233.7 79 16.0 3141 80 11.6 404.5 81 121.1 6582 82 4.9 63.0 83 2.7 113.0 84 2.3 116.6 85 5.2 192.1 86 0.3 164.7 87 0.4 133.8 88 0.1 1.8 89 0.2 3.4 90 1.2 29.0 91 44.7 4624 92 10.9 602.3 93 5.8 314.6 94 7.8 752.0 95 205 5041 96 0.7 24.6 97 0.6 33.3 98 0.9 116.4 99 4.4 230.9 100 1.4 4.8 101 32.7 390.0 102 103.5 538.7 103 0.5 136.7 104 17.7 766.1 105 328.6 743.0 106 316.4 429.6 107 126.9 1522 108 36% Inh. 8474 @ 1000 nM 109 0.7 7.8 110 0.2 1.8 111 0.7 16.5 112 0.4 7.9 113 58.1 470.5 114 50.6 2905 115 2.9 895.1 116 207.4 35% Inh. @ 10000 nM 117 0.2 13.0 118 1.9 386.7 119 51.6 1302 120 0.6 7.8 121 55.4 5344 122 368.7 2058 123 0.3 422.2 124 0.3 1.7 125 86.4 2501 126 2.6 2158 127 120.5 1158 128 0.3 2.4 129 4.1 469.9 130 1.2 78.7 131 11.8 66.0 132 6.7 242.6 133 4.3 558.5 134 123.6 4288 135 14.1 583.3 136 1.0 7.9 137 79.3 924.5 138 13.2 2257 139 16.8 2824 140 0.8 2723 141 24.1 1756 142 32% Inh. 7937 @ 1000 nM 143 984.1 7557 144 30% Inh. 7143 @ 1000 nM 145 32% Inh. 8046 @ 1000 nM 146 2.1 137.1 147 870.2 6333 148 385.1 4429 149 1.8 96.6 150 1.4 180.6
Measurement of A2A and A2B Antagonism in cAMP Cell-Based Assay - The ability of compounds to antagonize human A2A and A2B adenosine receptors was determined using a kit to measure changes in intracellular cyclic AMP levels (LANCE cAMP 384 Kit, Perkin Elmer, Cat. No. AD0264). HEK293 cells recombinantly expressing either human A2A or A2B receptors, previously frozen in Recovery Medium (Life Technologies, Cat. No. 12648-010) were thawed and diluted into stimulation buffer (HBSS (Hyclone SH 30268.01), 5 mM HEPES (Gibco 15630-106), 200 nM rolipram (Tocris, Cat. No. 0905), and 1.5% (V/v) BSA stabilizer (kit component). The cell suspension was centrifuged at 200×g for 10 min and then resuspended in stimulation buffer, supplemented with a 1:10 000 dilution of Alexa Fluor 647 anti-cAMP antibody, to a density of 6.0×105 cells/mL. A Labcyte Echo 550 acoustic dispenser was used to transfer up to 25 nL of test compound dissolved in DMSO into the wells of a dry Optiplate-384 plate (Perkin Elmer, Cat. No. 6008289). All subsequent liquid additions were performed using a multichannel pipettor. Next, 5 μL of the cell suspension was added to the wells of the Optiplate-384 and incubated for 30 min. at 37° C. and 5% CO2 in a humidified environment. After this time 5 μL of either 300 nM or 600 nM adenosine (Sigma Cat. No. A9251) for A2A and A2B respectively was added and incubated for 30 minutes at 37° C. and 5% CO2 in a humidified environment. At this time detection mix was prepared by combining the LANCE Eu-W8044 labeled streptavidin and Biotin-cAMP in detection buffer according to the manufacturers protocol. 10 μL of the detection mix was added to each well of the Optiplate-384 which was covered with a plate seal and incubated under ambient conditions for 2 hours prior to reading the plate using an Envision (Perkin Elmer, Waltham, Mass.) multimode plate reader. Data was normalized by defining minimal effect as stimulation in the presence of 0.25% (v/v) DMSO and maximal effect as stimulation in the presence of 1 μM ZM241385 (Cayman, Cat. No. 1036). Curve fitting of the percent effect data versus the log of compound concentration used a 4-parameter concentration response curve fitting algorithm to calculate IC50 values. Compound concentrations tested were 10,000, 3,333, 1,111, 370.4, 123.4, 41.2, 13.7, 4.6, 1.5 and 0.5 nM with 0.25% residual DMSO.
-
Example A2A IC50 c AMP (nM) A2B IC50 c AMP (nM) 151 3.8 56.9 152 5.9 371 153 7.4 719.8 154 1.2 974.1 155 23.9 1436 156 9.5 358.1 157 33.4 4481 158 1.1 32.9 159 1.0 29.3 160 8.7 647.8 161 38.9 3268 162 0.7 20.7 163 36.0 5306 164 1.9 47.7 165 0.8 6.4 166 20.0 2769 167 0.6 46.0 168 23.9 4723 169 96.5 3382 170 0.8 14.1 171 1.2 11.3 172 60.5 14% Inh. @ 10000 nM 173 20.7 2022 174 0.6 30.7 175 30.2 2004 176 0.9 10.2 177 154 3957 178 0.6 11.5 179 4.0 335.5 180 54.0 5342 181 16.0 5099 182 361.9 >10000 183 2.0 90.6 184 4.9 345.5 185 1.1 49.8 186 1.0 25.8 187 2.6 95.8 188 1.5 53.1 189 0.5 53.4 190 0.8 55.9 191 0.9 92.4 192 0.8 72.4 193 1.3 250.7 194 1.7 318.4 195 3.4 389.5 196 3.7 474.9 197 6.4 93.0 198 4.3 52.4 199 2.5 97.5 200 2.5 102.5 201 1.9 38.4 202 1.4 62.4 203 7.7 53.2 204 7.8 87.7 205 7.0 1146 206 13.0 4314 207 0.9 10.37 208 0.7 2799 209 0.7 634.9 210 16.2 35% Inh. @ 10000 nM 211 89.3 >10000 212 121.7 27% Inh. @ 10000 nM 213 330.8 >10000 214 0.5 34.09 215 0.4 27.5 216 1.0 159.7 217 1.1 161.3 218 235.8 5775 219 246.7 27% Inh. @ 10000 nM 220 20.4 30% Inh. @ 10000 nM 221 0.5 63 222 34.6 3277 223 0.7 46 224 0.4 13.1 225 0.4 12.1 226 17.6 1611 227 40.2 5071 228 0.8 16.1 229 1.0 6.6 230 32.9 723.7 231 121.5 3845 232 1.3 12.7 233 0.7 5.6 234 46.8 1195 235 438.8 4450 236 1.0 5.1 237 0.8 8.7 238 21.8 2438 239 75.1 10% Inh. @ 10000 nM 240 1.2 22.6 241 1.3 21.7 242 2.0 34.9 243 2.6 50.7 244 0.9 18.8 245 2.0 25.8 246 3.2 21.3 247 4.5 21.8 248 1.4 8.4 249 26.9 197.1 250 0.7 4.9 251 39.5 387.1 252 95.0 8157 253 123.1 >10000 254 1.5 10. 255 2.6 28.8 256 240.7 3892 257 540.6 25% Inh. @ 10000 nM 258 2.3 8.1 259 2.3 11.8 260 1.7 10.0 261 86.6 1473 262 2.2 23.9 263 26.0 510.8 264 3.0 14.3 265 1.3 4.5 266 64.2 579.6 267 175.1 1215 268 0.7 4.7 269 1.2 6.4 270 5.2 30.3 271 21.4 241.8 272 43.6 5800 273 1.2 26.7 274 0.7 70.5 275 15.6 2468
Claims (29)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US17/657,515 US12060357B2 (en) | 2018-11-30 | 2022-03-31 | 9-substituted amino triazolo quinazoline derivatives as adenosine receptor antagonists, pharmaceutical compositions and their use |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201862774077P | 2018-11-30 | 2018-11-30 | |
US16/695,367 US11312719B2 (en) | 2018-11-30 | 2019-11-26 | 9-substituted amino triazolo quinazoline derivatives as adenosine receptor antagonists, pharmaceutical compositions and their use |
US17/657,515 US12060357B2 (en) | 2018-11-30 | 2022-03-31 | 9-substituted amino triazolo quinazoline derivatives as adenosine receptor antagonists, pharmaceutical compositions and their use |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US16/695,367 Division US11312719B2 (en) | 2018-11-30 | 2019-11-26 | 9-substituted amino triazolo quinazoline derivatives as adenosine receptor antagonists, pharmaceutical compositions and their use |
Publications (2)
Publication Number | Publication Date |
---|---|
US20220220117A1 true US20220220117A1 (en) | 2022-07-14 |
US12060357B2 US12060357B2 (en) | 2024-08-13 |
Family
ID=69005832
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US16/695,367 Active 2040-03-20 US11312719B2 (en) | 2018-11-30 | 2019-11-26 | 9-substituted amino triazolo quinazoline derivatives as adenosine receptor antagonists, pharmaceutical compositions and their use |
US17/657,515 Active US12060357B2 (en) | 2018-11-30 | 2022-03-31 | 9-substituted amino triazolo quinazoline derivatives as adenosine receptor antagonists, pharmaceutical compositions and their use |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US16/695,367 Active 2040-03-20 US11312719B2 (en) | 2018-11-30 | 2019-11-26 | 9-substituted amino triazolo quinazoline derivatives as adenosine receptor antagonists, pharmaceutical compositions and their use |
Country Status (25)
Country | Link |
---|---|
US (2) | US11312719B2 (en) |
EP (1) | EP3886988A1 (en) |
JP (1) | JP7241871B2 (en) |
KR (1) | KR102653800B1 (en) |
CN (1) | CN113329791A (en) |
AR (1) | AR117164A1 (en) |
AU (1) | AU2019385905B2 (en) |
BR (1) | BR112021010427B1 (en) |
CA (1) | CA3120862C (en) |
CL (1) | CL2021001406A1 (en) |
CO (1) | CO2021006888A2 (en) |
CR (1) | CR20210271A (en) |
DO (1) | DOP2021000104A (en) |
EA (1) | EA202191498A1 (en) |
EC (1) | ECSP21036982A (en) |
IL (1) | IL283334A (en) |
JO (2) | JOP20210117A1 (en) |
MA (1) | MA54298A (en) |
MX (1) | MX2021006329A (en) |
NI (1) | NI202100043A (en) |
PE (1) | PE20211768A1 (en) |
PH (1) | PH12021551196A1 (en) |
SG (1) | SG11202105180PA (en) |
TW (1) | TW202039496A (en) |
WO (1) | WO2020112700A1 (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20230054411A1 (en) * | 2018-11-30 | 2023-02-23 | Merck Sharp & Dohme Corp. | 7-, 8-, and 10-SUBSTITUTED AMINO TRIAZOLO QUINAZOLINE DERIVATIVES AS ADENOSINE RECEPTOR ANTAGONISTS, PHARMACEUTICAL COMPOSITIONS AND THEIR USE |
US12037354B2 (en) | 2018-11-30 | 2024-07-16 | Vectivbio Comet Ag | Cyclic pantetheine derivatives and uses thereof |
Families Citing this family (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ES2437327T3 (en) | 2007-06-18 | 2014-01-10 | Merck Sharp & Dohme B.V. | Antibodies for the human programmed PD-1 receptor of programmed death |
US11466017B2 (en) | 2011-03-10 | 2022-10-11 | Board Of Regents, The University Of Texas System | Heterocyclic inhibitors of PTPN11 |
AU2017274199B2 (en) | 2016-05-31 | 2021-09-23 | Board Of Regents, The University Of Texas System | Heterocyclic inhibitors of PTPN11 |
WO2019213318A1 (en) | 2018-05-02 | 2019-11-07 | Board Of Regents, The University Of Texas System | Substituted heterocyclic inhibitors of ptpn11 |
JP2021534124A (en) | 2018-08-10 | 2021-12-09 | ナビール ファーマ,インコーポレイティド | 6- (4-Amino-3-methyl-2-oxa-8-azaspiro [4.5] decane-8-yl) -3- (2,3-dichlorophenyl) as an inhibitor of PTPN11 (SHP2) for the treatment of cancer -2-Methylpyrimidine-4 (3H) -one derivative and related compounds |
WO2023158626A1 (en) * | 2022-02-16 | 2023-08-24 | Merck Sharp & Dohme Llc | Adenosine receptor antagonists, pharmaceutical compositions and their use thereof |
WO2023201267A1 (en) | 2022-04-13 | 2023-10-19 | Gilead Sciences, Inc. | Combination therapy for treating trop-2 expressing cancers |
WO2024118460A1 (en) * | 2022-11-29 | 2024-06-06 | Merck Sharp & Dohme Llc | Adenosine a2a and a2b receptor antagonists, pharmaceutical compositions and use thereof |
Family Cites Families (62)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3957766A (en) | 1970-06-19 | 1976-05-18 | Boehringer Mannheim G.M.B.H. | Novel nitrofuran compounds and pharmaceutical compositions |
DE2109577A1 (en) | 1971-03-01 | 1972-09-14 | Boehringer Mannheim Gmbh | 5-nitrofuran and 5-nitrothiophen derivs - a5-antimicrobials |
US4713383A (en) | 1984-10-01 | 1987-12-15 | Ciba-Geigy Corporation | Triazoloquinazoline compounds, and their methods of preparation, pharmaceutical compositions, and uses |
GB9524395D0 (en) | 1995-11-29 | 1996-01-31 | Nickerson Biocem Ltd | Promoters |
DE19629378A1 (en) | 1996-07-20 | 1998-01-29 | Boehringer Ingelheim Kg | New triazolopurines, process for their preparation and their use as medicaments |
SK287748B6 (en) | 2000-05-26 | 2011-08-04 | Schering Corporation | Substituted 5-amino-pyrazolo[4,3-e]-1,2,4,triazolo[1,5-c]- pyrimidines, method for the production thereof, pharmaceutical composition comprising same and their use |
US6759759B2 (en) | 2000-08-29 | 2004-07-06 | Tamagawa Seiki Kabushiki Kaisha | Rotary contactless connector and non-rotary contactless connector |
PE20030477A1 (en) | 2001-10-15 | 2003-06-06 | Schering Corp | ADENOSINE A2a RECEPTOR ANTAGONISTS |
AR038366A1 (en) | 2001-11-30 | 2005-01-12 | Schering Corp | 1,2,4-TRIAZOLO COMPOUNDS [1,5-C] SUBSTITUTED PYRIMIDINS, ANTAGONISTS OF THE ADENOSINE A2A RECEPTOR, PHARMACEUTICAL COMPOSITIONS, THE USE OF SUCH COMPOUNDS FOR THE MANUFACTURE OF A MEDICINAL PRODUCT FOR THE PROCESSING OF DISEASE SYSTEMS AND CENTRAL SYSTEMS A KIT THAT INCLUDES COMBINATION |
WO2003048165A1 (en) | 2001-11-30 | 2003-06-12 | Schering Corporation | ADENOSINE A2a RECEPTOR ANTAGONISTS |
AU2003281200A1 (en) | 2002-07-03 | 2004-01-23 | Tasuku Honjo | Immunopotentiating compositions |
CA2500228A1 (en) | 2002-09-24 | 2004-04-08 | Kyowa Hakko Kogyo Co., Ltd. | [1,2,4]-triazolo[1,5-c]pyrimidine derivative |
CA2508660C (en) | 2002-12-23 | 2013-08-20 | Wyeth | Antibodies against pd-1 and uses therefor |
EP2270051B1 (en) | 2003-01-23 | 2019-05-15 | Ono Pharmaceutical Co., Ltd. | Antibody specific for human PD-1 and CD3 |
WO2004092177A1 (en) | 2003-04-09 | 2004-10-28 | Biogen Idec Ma Inc. | Triazolopyrazines and methods of making and using the same |
EP1678182B1 (en) | 2003-10-28 | 2007-02-07 | Schering Corporation | Process for preparing substituted 5-amino-pyrazolo- [4,3-e]-1,2,4-triazolo [1,5-c]pyrimidines |
DE602004009962T2 (en) | 2003-12-01 | 2008-08-28 | Schering Corp. | PROCESS FOR PREPARING SUBSTITUTED 5-AMINOPYRAZOLOÄ4,3-EÜ-1,2,4-TRIAZOLOÄ1,5-CYPYRIMIDINES |
WO2005103055A1 (en) | 2004-04-21 | 2005-11-03 | Schering Corporation | PYRAZOLO-[4,3-e]-1,2,4-TRIAZOLO-[1,5-c]-PYRIMIDINE ADENOSINE A2A RECEPTOR ANTAGONISTS |
US7472383B2 (en) | 2004-08-13 | 2008-12-30 | Sun Microsystems, Inc. | System and method for providing exceptional flow control in protected code through memory layers |
WO2006068954A2 (en) | 2004-12-21 | 2006-06-29 | Schering Corporation | PYRAZOLO[1,5-A]PYRIMIDINE ADENOSINE A2a RECEPTOR ANTAGONISTS |
NZ563193A (en) | 2005-05-09 | 2010-05-28 | Ono Pharmaceutical Co | Human monoclonal antibodies to programmed death 1(PD-1) and methods for treating cancer using anti-PD-1 antibodies alone or in combination with other immunotherapeutics |
SI1907424T1 (en) | 2005-07-01 | 2015-12-31 | E. R. Squibb & Sons, L.L.C. | Human monoclonal antibodies to programmed death ligand 1 (pd-l1) |
WO2007035542A1 (en) | 2005-09-19 | 2007-03-29 | Schering Corporation | 2-HETEROARYL-PYRAZOLO-[4, 3-e]-1, 2, 4-TRIAZOLO-[1,5-c]-PYRIMIDINE AS ADENOSINE A2a RECEPTOR ANTAGONISTS |
AR056080A1 (en) | 2005-09-23 | 2007-09-19 | Schering Corp | 7- [2- [4- (6-FLUORO-3-METIL-1,2-BENCIOSOXAZOL-5-IL) -1-PIPERAZINIL] ETIL] -2- (1-PROPINYL) -7H-PIRAZOL- [4, 3-E] - [1,2,4] -TRIAZOL- [1,5-C] -PIRIMIDIN-5-AMINE |
MX2009000104A (en) | 2006-06-26 | 2009-01-23 | Schering Corp | Adenosine a2a receptor antagonists. |
US7691869B2 (en) | 2007-03-30 | 2010-04-06 | King Pharmaceuticals Research And Development, Inc. | Pyrrolotriazolopyrimidine derivatives, pharmaceutical compositions containing them and methods of treating conditions and diseases mediated by the adenosine A2A receptor activity |
HUP0700395A2 (en) | 2007-06-07 | 2009-03-02 | Sanofi Aventis | Substituted [1,2,4] triazolo [1,5-a] quinolines, process for their preparation, pharmaceutical compositions thereof, and intermediates |
ES2437327T3 (en) | 2007-06-18 | 2014-01-10 | Merck Sharp & Dohme B.V. | Antibodies for the human programmed PD-1 receptor of programmed death |
PE20091101A1 (en) | 2007-12-18 | 2009-07-26 | Pharminox Ltd | 3-SUBSTITUTED-4-OXO-3,4-DIHYDRO-IMIDAZO [5,1-d] [1,2,3,5-TETRACINE-8-CARBOXYL ACID AMIDES AND ITS USE |
EP2282999B1 (en) | 2008-03-04 | 2014-05-21 | Merck Sharp & Dohme Corp. | Amino-quinoxaline and amino-quinoline compounds for use as adenosine a2a receptor antagonists |
EP2262837A4 (en) | 2008-03-12 | 2011-04-06 | Merck Sharp & Dohme | Pd-1 binding proteins |
US20110159023A1 (en) | 2008-08-25 | 2011-06-30 | Solomon Langermann | Pd-1 antagonists and methods for treating infectious disease |
SI2342226T1 (en) | 2008-09-26 | 2016-11-30 | Dana-Farber Cancer Institute Inc. | Human anti-pd-1, pd-l1, and pd-l2 antibodies and uses thereof |
CN114835812A (en) | 2008-12-09 | 2022-08-02 | 霍夫曼-拉罗奇有限公司 | anti-PD-L1 antibodies and their use for enhancing T cell function |
US8435994B2 (en) | 2009-11-16 | 2013-05-07 | Merck Sharp & Dohme Corp. | Substituted [1,2,4]triazolo[4,3-alpha]quinoxalines as adenosine A2a receptor antagonists |
JP2013512251A (en) | 2009-11-24 | 2013-04-11 | アンプリミューン、インコーポレーテッド | Simultaneous inhibition of PD-L1 / PD-L2 |
WO2012135084A1 (en) | 2011-03-31 | 2012-10-04 | Merck Sharp & Dohme Corp. | METABOLITES OF 2-(FURAN-2-YL)-7-(2-(4-(4-(2-METHOXYETHOXY)PHENYL)PIPERAZIN-1-YL)ETHYL)-7H-PYRAZOLO[4,3-e][1,2,4]TRIAZOLO[1,5-c]PYRIMIDIN-5-AMINE AND THEIR UTILITY AS ADENOSINE A2a RECEPTOR ANTAGONISTS |
BR112014002353B1 (en) | 2011-08-01 | 2022-09-27 | Genentech, Inc | USES OF PD-1 AXIS BINDING ANTAGONISTS AND MEK INHIBITORS, PHARMACEUTICAL COMPOSITIONS, AND KIT |
US8751477B2 (en) | 2012-10-05 | 2014-06-10 | Iac Search & Media, Inc. | Quality control system for providing results in response to queries |
US9495379B2 (en) | 2012-10-08 | 2016-11-15 | Veritas Technologies Llc | Locality aware, two-level fingerprint caching |
WO2014101113A1 (en) | 2012-12-28 | 2014-07-03 | Merck Sharp & Dohme Corp. | Piperazine-substituted 7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-5-amine compounds with a2a antagonist properties |
WO2014101120A1 (en) | 2012-12-28 | 2014-07-03 | Merck Sharp & Dohme Corp. | Heterobicyclo-substituted-7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-5-amine compounds with a2a antagonist properties |
WO2015027431A1 (en) | 2013-08-29 | 2015-03-05 | Merck Sharp & Dohme Corp. | 2,2-difluorodioxolo a2a receptor antagonists |
AU2015350315B2 (en) | 2014-11-18 | 2020-06-25 | Merck Sharp & Dohme Corp. | Aminopyrazine compounds with A2A antagonist properties |
EP3227299B1 (en) | 2014-12-04 | 2021-05-26 | Merck Sharp & Dohme Corp. | Formulation inhibiting effects of low acid environment |
WO2016126570A1 (en) | 2015-02-06 | 2016-08-11 | Merck Sharp & Dohme Corp. | Aminoquinazoline compounds as a2a antagonist |
EP3307067B1 (en) | 2015-06-11 | 2022-11-02 | Merck Sharp & Dohme LLC | Aminopyrazine compounds with a2a antagonist properties |
WO2016209787A1 (en) | 2015-06-26 | 2016-12-29 | Merck Sharp & Dohme Corp. | Sustained release formulation and tablets prepared therefrom |
WO2017008205A1 (en) | 2015-07-10 | 2017-01-19 | Merck Sharp & Dohme Corp. | Substituted aminoquinazoline compounds as a2a antagonist |
SI3570844T1 (en) * | 2017-01-20 | 2024-01-31 | Arcus Biosciences, Inc. | Azolopyrimidine for the treatment of cancer-related disorders |
CN109963854B (en) | 2017-03-16 | 2022-04-12 | 江苏恒瑞医药股份有限公司 | Heteroaryl [4,3-c ] pyrimidine-5-amine derivative, preparation method and application thereof in medicine |
WO2018184590A1 (en) | 2017-04-07 | 2018-10-11 | 南京明德新药研发股份有限公司 | [1,2,4]triazolo[1,5-c]pyrimidine derivative as a2a receptor inhibitor |
CN110809577A (en) | 2017-06-30 | 2020-02-18 | 雷沃医疗有限公司 | Modulators of adenosine A2A receptor |
EP3723754A4 (en) | 2017-12-13 | 2021-05-19 | Merck Sharp & Dohme Corp. | Imidazo [1,2-c] quinazolin-5-amine compounds with a2a antagonist properties |
EP3810610A1 (en) | 2018-05-18 | 2021-04-28 | Incyte Corporation | Fused pyrimidine derivatives as a2a / a2b inhibitors |
JP2021534124A (en) | 2018-08-10 | 2021-12-09 | ナビール ファーマ,インコーポレイティド | 6- (4-Amino-3-methyl-2-oxa-8-azaspiro [4.5] decane-8-yl) -3- (2,3-dichlorophenyl) as an inhibitor of PTPN11 (SHP2) for the treatment of cancer -2-Methylpyrimidine-4 (3H) -one derivative and related compounds |
KR20210093964A (en) | 2018-11-20 | 2021-07-28 | 머크 샤프 앤드 돔 코포레이션 | Substituted amino triazolopyrimidine and amino triazolopyrazine adenosine receptor antagonists, pharmaceutical compositions and uses thereof |
US20220040184A1 (en) | 2018-11-20 | 2022-02-10 | Merck Sharp Dohme Corp. | Substituted amino triazolopyrimidine and amino triazolopyrazine adenosine receptor antagonists, pharmaceutical compositions and their use |
AR117183A1 (en) | 2018-11-30 | 2021-07-14 | Syngenta Crop Protection Ag | THIAZOL DERIVATIVES MICROBIOCIDES |
US10870663B2 (en) | 2018-11-30 | 2020-12-22 | Glaxosmithkline Intellectual Property Development Limited | Compounds useful in HIV therapy |
AR117200A1 (en) | 2018-11-30 | 2021-07-21 | Syngenta Participations Ag | THIAZOL DERIVATIVES MICROBIOCIDES |
JP2022511778A (en) | 2018-11-30 | 2022-02-01 | メルク・シャープ・アンド・ドーム・コーポレーション | 7-, 8- and 10-substituted aminotriazoloquinazoline derivatives, pharmaceutical compositions and their use as adenosine receptor antagonists |
-
2019
- 2019-11-26 CA CA3120862A patent/CA3120862C/en active Active
- 2019-11-26 AR ARP190103450A patent/AR117164A1/en unknown
- 2019-11-26 CN CN201980090487.8A patent/CN113329791A/en active Pending
- 2019-11-26 JO JOP/2021/0117A patent/JOP20210117A1/en unknown
- 2019-11-26 PE PE2021000757A patent/PE20211768A1/en unknown
- 2019-11-26 EP EP19827893.9A patent/EP3886988A1/en active Pending
- 2019-11-26 KR KR1020217019802A patent/KR102653800B1/en active IP Right Grant
- 2019-11-26 MA MA054298A patent/MA54298A/en unknown
- 2019-11-26 EA EA202191498A patent/EA202191498A1/en unknown
- 2019-11-26 JO JOP/2021/0116A patent/JOP20210116A1/en unknown
- 2019-11-26 AU AU2019385905A patent/AU2019385905B2/en active Active
- 2019-11-26 BR BR112021010427-5A patent/BR112021010427B1/en active IP Right Grant
- 2019-11-26 CR CR20210271A patent/CR20210271A/en unknown
- 2019-11-26 SG SG11202105180PA patent/SG11202105180PA/en unknown
- 2019-11-26 TW TW108142874A patent/TW202039496A/en unknown
- 2019-11-26 MX MX2021006329A patent/MX2021006329A/en unknown
- 2019-11-26 US US16/695,367 patent/US11312719B2/en active Active
- 2019-11-26 JP JP2021530114A patent/JP7241871B2/en active Active
- 2019-11-26 WO PCT/US2019/063136 patent/WO2020112700A1/en active Application Filing
-
2021
- 2021-05-20 IL IL283334A patent/IL283334A/en unknown
- 2021-05-24 NI NI202100043A patent/NI202100043A/en unknown
- 2021-05-25 PH PH12021551196A patent/PH12021551196A1/en unknown
- 2021-05-25 EC ECSENADI202136982A patent/ECSP21036982A/en unknown
- 2021-05-26 CO CONC2021/0006888A patent/CO2021006888A2/en unknown
- 2021-05-27 CL CL2021001406A patent/CL2021001406A1/en unknown
- 2021-05-27 DO DO2021000104A patent/DOP2021000104A/en unknown
-
2022
- 2022-03-31 US US17/657,515 patent/US12060357B2/en active Active
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20230054411A1 (en) * | 2018-11-30 | 2023-02-23 | Merck Sharp & Dohme Corp. | 7-, 8-, and 10-SUBSTITUTED AMINO TRIAZOLO QUINAZOLINE DERIVATIVES AS ADENOSINE RECEPTOR ANTAGONISTS, PHARMACEUTICAL COMPOSITIONS AND THEIR USE |
US12037354B2 (en) | 2018-11-30 | 2024-07-16 | Vectivbio Comet Ag | Cyclic pantetheine derivatives and uses thereof |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US12060357B2 (en) | 9-substituted amino triazolo quinazoline derivatives as adenosine receptor antagonists, pharmaceutical compositions and their use | |
US9868720B2 (en) | C-linked heterocycloaklyl substituted pyrimidines and their uses | |
JP6242885B2 (en) | 5-azaindazole compounds and methods of use | |
US9556197B2 (en) | Furo- and thieno-pyridine carboxamide compounds useful as pim kinase inhibitors | |
WO2020106560A1 (en) | Substituted amino triazolopyrimidine and amino triazolopyrazine adenosine receptor antagonists, pharmaceutical compositions and their use | |
US20230054411A1 (en) | 7-, 8-, and 10-SUBSTITUTED AMINO TRIAZOLO QUINAZOLINE DERIVATIVES AS ADENOSINE RECEPTOR ANTAGONISTS, PHARMACEUTICAL COMPOSITIONS AND THEIR USE | |
US20230399327A1 (en) | High activity hpk1 kinase inhibitor | |
US20210395255A1 (en) | Substituted amino triazolopyrimidine and amino triazolopyrazine adenosine receptor antagonists, pharmaceutical compositions and their use | |
US20230322785A1 (en) | Adenosine a2a and a2b receptor dual antagonists for immuno-oncology | |
US20240076297A1 (en) | Adenosine a2a and a2b receptor dual antagonists for immuno-oncology | |
EA043752B1 (en) | 9-Substituted aminotriazoloquinazoline derivatives as adenosine receptor antagonists, pharmaceutical compositions and their use | |
WO2023158626A1 (en) | Adenosine receptor antagonists, pharmaceutical compositions and their use thereof |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AS | Assignment |
Owner name: MERCK SHARP & DOHME CORP., NEW JERSEY Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:LARSEN, MATTHEW A.;ALI, AMJAD;CUMMING, JARED;AND OTHERS;SIGNING DATES FROM 20191021 TO 20191118;REEL/FRAME:059601/0414 |
|
FEPP | Fee payment procedure |
Free format text: ENTITY STATUS SET TO UNDISCOUNTED (ORIGINAL EVENT CODE: BIG.); ENTITY STATUS OF PATENT OWNER: LARGE ENTITY |
|
STPP | Information on status: patent application and granting procedure in general |
Free format text: DOCKETED NEW CASE - READY FOR EXAMINATION |
|
AS | Assignment |
Owner name: MERCK SHARP & DOHME LLC, NEW JERSEY Free format text: MERGER;ASSIGNOR:MERCK SHARP & DOHME CORP.;REEL/FRAME:060146/0381 Effective date: 20220407 |
|
AS | Assignment |
Owner name: MERCK SHARP & DOHME LLC, NEW JERSEY Free format text: MERGER;ASSIGNOR:MERCK SHARP & DOHME CORP.;REEL/FRAME:061102/0145 Effective date: 20220407 |
|
STPP | Information on status: patent application and granting procedure in general |
Free format text: NON FINAL ACTION MAILED |
|
STPP | Information on status: patent application and granting procedure in general |
Free format text: RESPONSE TO NON-FINAL OFFICE ACTION ENTERED AND FORWARDED TO EXAMINER |
|
STPP | Information on status: patent application and granting procedure in general |
Free format text: NOTICE OF ALLOWANCE MAILED -- APPLICATION RECEIVED IN OFFICE OF PUBLICATIONS |
|
STPP | Information on status: patent application and granting procedure in general |
Free format text: PUBLICATIONS -- ISSUE FEE PAYMENT VERIFIED |
|
STCF | Information on status: patent grant |
Free format text: PATENTED CASE |